Ankylosing spondylitis (AS) is a progressive multisystem chronic inflammatory disorder. The hallmark of this pathological process is a progressive fusion of the zygapophyseal joints and disc spaces of the axial skeleton, leading to a rigid kyphotic deformity and positive sagittal balance. The ankylosed spine is unable to accommodate normal mechanical forces, rendering it brittle and susceptible to injury. Traumatic hyperextension injury of the cervical spine leading to atlantoaxial subluxation (AAS) in AS patients can often be fatal. We report a non-traumatic mechanism of injury in AS progressing to AAS attributable to persistent hyperextension, which resulted in fatal migration of C2 through the foramen magnum. Cite this article: Bone Joint J 2013;95-B:206–9

Aims. The conventionally described mechanism of distal biceps tendon rupture (DBTR) is of a ‘considerable extension force suddenly applied to a resisting, actively flexed forearm’. This has been commonly paraphrased as an ‘eccentric contracture to a flexed elbow’. Both definitions have been frequently used in the literature with little objective analysis or citation. The aim of the present study was to use video footage of real time distal biceps ruptures to revisit and objectively define the mechanism of injury. Methods. An online search identified 61 videos reporting a DBTR. Videos were independently reviewed by three surgeons to assess forearm rotation, elbow flexion, shoulder position, and type of muscle contraction being exerted at the time of rupture. Prospective data on mechanism of injury and arm position was also collected concurrently for 22 consecutive patients diagnosed with an acute DBTR in order to corroborate the video analysis. Results. Four videos were excluded, leaving 57 for final analysis. Mechanisms of injury included deadlift, bicep curls, calisthenics, arm wrestling, heavy lifting, and boxing. In all, 98% of ruptures occurred with the arm in supination and 89% occurred at 0° to 10° of elbow flexion. Regarding muscle activity, 88% occurred during isometric contraction, 7% during eccentric contraction, and 5% during concentric contraction. Interobserver correlation scores were calculated as 0.66 to 0.89 using the free-marginal Fleiss Kappa tool. The prospectively collected patient data was consistent with the video analysis, with 82% of injuries occurring in supination and 95% in relative elbow extension. Conclusion. Contrary to the classically described injury mechanism, in this study the usual arm position during DBTR was forearm supination and elbow extension, and the muscle contraction was typically isometric. This was demonstrated for both video analysis and ‘real’ patients across a range of activities leading to rupture. Cite this article: Bone Jt Open 2022;3(10):826–831

Aims. This study aimed to demonstrate the promoting effect of elastic fixation on fracture, and further explore its mechanism at the gene and protein expression levels. Methods. A closed tibial fracture model was established using 12 male Japanese white rabbits, and divided into elastic and stiff fixation groups based on different fixation methods. Two weeks after the operation, a radiograph and pathological examination of callus tissue were used to evaluate fracture healing. Then, the differentially expressed proteins (DEPs) were examined in the callus using proteomics. Finally, in vitro cell experiments were conducted to investigate hub proteins involved in this process. Results. Mean callus volume was larger in the elastic fixation group (1,755 mm. 3. (standard error of the mean (SEM) 297)) than in the stiff fixation group (258 mm. 3. (SEM 65)). Pathological observation found that the expression levels of osterix (OSX), collagen, type I, alpha 1 (COL1α1), and alkaline phosphatase (ALP) in the callus of the elastic fixation group were higher than those of the stiff fixation group. The protein sequence of the callus revealed 199 DEPs, 124 of which were highly expressed in the elastic fixation group. In the in vitro study, it was observed that a stress of 200 g led to upregulation of thrombospondin 1 (THBS1) and osteoglycin (OGN) expression in bone marrow mesenchymal stem cells (BMSCs). Additionally, these genes were found to be upregulated during the osteogenic differentiation process of the BMSCs. Conclusion. Elastic fixation can promote fracture healing and osteoblast differentiation in callus, and the ability of elastic fixation to promote osteogenic differentiation of BMSCs may be achieved by upregulating genes such as THBS1 and OGN. Cite this article: Bone Joint Res 2024;13(10):559–572

Aims. Kashin-Beck disease (KBD) is a kind of chronic osteochondropathy, thought to be caused by environmental risk factors such as T-2 toxin. However, the exact aetiology of KBD remains unclear. In this study, we explored the functional relevance and biological mechanism of cartilage oligosaccharide matrix protein (COMP) in the articular cartilage damage of KBD. Methods. The articular cartilage specimens were collected from five KBD patients and five control subjects for cell culture. The messenger RNA (mRNA) and protein expression levels were detected by quantitative reverse transcription PCR (qRT-PCR) and western blot. The survival rate of C28/I2 chondrocyte cell line was detected by MTT assay after T-2 toxin intervention. The cell viability and mRNA expression levels of apoptosis related genes between COMP-overexpression groups and control groups were examined after cell transfection. Results. The mRNA and protein expression levels of COMP were significantly lower in KBD chondrocytes than control chondrocytes. After the T-2 toxin intervention, the COMP mRNA expression of C28/I2 chondrocyte reduced and the protein level of COMP in three intervention groups was significantly lower than in the control group. MTT assay showed that the survival rate of COMP overexpression KBD chondrocytes were notably higher than in the blank control group. The mRNA expression levels of Survivin, SOX9, Caspase-3, and type II collagen were also significantly different among COMP overexpression, negative control, and blank control groups. Conclusion. Our study results confirmed the functional relevance of COMP with KBD. COMP may play an important role in the excessive chondrocytes apoptosis of KBD patients. Cite this article: Bone Joint Res 2020;9(9):578–586

Abnormal sagittal kinematics after total knee replacement (TKR) can adversely affect functional outcome. Two important determinants of knee kinematics are component geometry and the presence or absence of a posterior-stabilising mechanism (cam-post). We investigated the influence of these variables by comparing the kinematics of a TKR with a polyradial femur with a single radius design, both with and without a cam-post mechanism. We assessed 55 patients, subdivided into four groups, who had undergone a TKR one year earlier by using an established fluoroscopy protocol in order to examine their kinematics in vivo. The kinematic profile was obtained by measuring the patellar tendon angle through the functional knee flexion range (0° to 90°) and the results compared with 14 normal knees. All designs of TKR had abnormal sagittal kinematics compared with the normal knee. There was a significant (p < 0.05) difference between those of the two TKRs near to full extension. The presence of the cam-post mechanism did not influence the kinematics for either TKR design. These differences suggest that surface geometry is a stronger determinant of kinematics than the presence or absence of a cam-post mechanism for these two designs. This may be because the cam-post mechanism is ineffective

Aims. Methicillin-resistant Staphylococcus aureus (MRSA) can cause wound infections via a ‘Trojan Horse’ mechanism, in which neutrophils engulf intestinal MRSA and travel to the wound, releasing MRSA after apoptosis. The possible role of intestinal MRSA in prosthetic joint infection (PJI) is unknown. Methods. Rats underwent intestinal colonization with green fluorescent protein (GFP)-tagged MRSA by gavage and an intra-articular wire was then surgically implanted. After ten days, the presence of PJI was determined by bacterial cultures of the distal femur, joint capsule, and implant. We excluded several other possibilities for PJI development. Intraoperative contamination was excluded by culturing the specimen obtained from surgical site. Extracellular bacteraemia-associated PJI was excluded by comparing with the infection rate after intravenous injection of MRSA or MRSA-carrying neutrophils. To further support this theory, we tested the efficacy of prophylactic membrane-permeable and non-membrane-permeable antibiotics in this model. Results. After undergoing knee surgery eight or 72 hours after colonization, five out of 20 rats (25.0%) and two out of 20 rats (10.0%) developed PJI, respectively. Strikingly, 11 out of 20 rats (55.0%) developed PJI after intravenous injection of MRSA-carrying neutrophils that were isolated from rats with intestinal MRSA colonization. None of the rats receiving intravenous injections of MRSA developed PJI. These results suggest that intestinal MRSA carried by neutrophils could cause PJI in our rat model. Ten out of 20 (50.0%) rats treated with non-membrane-permeable gentamicin developed PJI, whereas only one out of 20 (5.0%) rats treated with membrane-permeable linezolid developed PJI. Conclusion. Neutrophils as carriers of intestinal MRSA may play an important role in PJI development. Cite this article:Bone Joint Res. 2020;9(4):152–161

Disruption of the extensor mechanism in total knee arthroplasty may occur by tubercle avulsion, patellar or quadriceps tendon rupture, or patella fracture, and whether occurring intra-operatively or post-operatively can be difficult to manage and is associated with a significant rate of failure and associated complications. This surgery is frequently performed in compromised tissues, and repairs must frequently be protected with cerclage wiring and/or augmentation with local tendon (semi-tendinosis, gracilis) which may also be used to treat soft-tissue loss in the face of chronic disruption. Quadriceps rupture may be treated with conservative therapy if the patient retains active extension. Component loosening or loss of active extension of 20° or greater are clear indications for surgical treatment of patellar fracture. Acute patellar tendon disruption may be treated by primary repair. Chronic extensor failure is often complicated by tissue loss and retraction can be treated with medial gastrocnemius flaps, achilles tendon allografts, and complete extensor mechanism allografts. Attention to fixing the graft in full extension is mandatory to prevent severe extensor lag as the graft stretches out over time

Aims

Paediatric triplane fractures and adult trimalleolar ankle fractures both arise from a supination external rotation injury. By relating the experience of adult to paediatric fractures, clarification has been sought on the sequence of injury, ligament involvement, and fracture pattern of triplane fractures. This study explores the similarities between triplane and trimalleolar fractures for each stage of the Lauge-Hansen classification, with the aim of aiding reduction and fixation techniques.

1. The influence of various methods of preserving bone on the calcifying mechanism of the tibial epiphysial cartilage of rachitic rats was studied. An in vitro calcification technique was employed. 2. Preservation by deep freezing, aqueous merthiolate, boiling, or acetone inactivated the calcifying mechanism. 3. The inactivation was reversed with calcium ions, most readily in the deep-frozen bones, less readily in the merthiolate treated bones, still less readily in the acetone stored bones, and least in boiled bones. 4. Exposure to calcium ions before preservation in the deep-freeze chest prevented inactivation. 5. The inactivation, reactivation and survival of the calcifying mechanism were confirmed by metachromasia studies. 6. The theory of the mode of action of calcium chloride on reactivation and survival of the calcifying mechanism is presented

Anterior knee pain due to dysplasia of the extensor mechanism is common. We have studied 137 knees (103 patients) in order to identify a rapid and reproducible radiological feature which would indicate the need for further analysis. Overall, 67 knees (49%) had at least one radiological abnormality; 70 (51%) were considered normal. There were five cases of Dejour type-3 dysplasia of the femoral trochlea, nine of type-2 and 12 of type-1. There were 49 cases of patella alta and five of patella infera. Four knees had an abnormal lateral patellofemoral angle (patellar tilt), and in 15 knees there was more than one abnormality. Classification of trochlear dysplasia was difficult and showed poor reproducibility. This was also true for the measurement of the lateral patellofemoral angle. Patellar height was more easily measured but took time. The sulcus angle is an easily and rapidly measurable feature which was reproducible and was closely related to other features of dysplasia of the extensor mechanism. The finding of a normal sulcus angle suggested that seeking other radiological evidence of malalignment of the extensor mechanism was unlikely to reveal additional useful information. The severity of other features of dysplasia of the extensor mechanism correlated with increasing sulcus angle

Deficiency of the abductor mechanism is a well-recognised cause of pain and limping after total hip replacement (THR). This can be found incidentally at the time of surgery, or it may arise as a result of damage to the superior gluteal nerve intra-operatively, or after surgery owing to mechanical failure of the abductor muscle repair or its detachment from the greater trochanter. The incidence of abductor failure has been reported as high as 20% in some studies. The management of this condition remains a dilemma for the treating surgeon. We review the current state of knowledge concerning post-THR abductor deficiency, including the aetiology, diagnosis and management, and the outcomes of surgery for this condition. Cite this article: Bone Joint J 2013;95-B:343–7

Tendon is a bradytrophic and hypovascular tissue, hence, healing remains a major challenge. The molecular key events involved in successful repair have to be unravelled to develop novel strategies that reduce the risk of unfavourable outcomes such as non-healing, adhesion formation, and scarring. This review will consider the diverse pathophysiological features of tendon-derived cells that lead to failed healing, including misrouted differentiation (e.g. de- or transdifferentiation) and premature cell senescence, as well as the loss of functional progenitors. Many of these features can be attributed to disturbed cell-extracellular matrix (ECM) or unbalanced soluble mediators involving not only resident tendon cells, but also the cross-talk with immigrating immune cell populations. Unrestrained post-traumatic inflammation could hinder successful healing. Pro-angiogenic mediators trigger hypervascularization and lead to persistence of an immature repair tissue, which does not provide sufficient mechano-competence. Tendon repair tissue needs to achieve an ECM composition, structure, strength, and stiffness that resembles the undamaged highly hierarchically ordered tendon ECM. Adequate mechano-sensation and -transduction by tendon cells orchestrate ECM synthesis, stabilization by cross-linking, and remodelling as a prerequisite for the adaptation to the increased mechanical challenges during healing. Lastly, this review will discuss, from the cell biological point of view, possible optimization strategies for augmenting Achilles tendon (AT) healing outcomes, including adapted mechanostimulation and novel approaches by restraining neoangiogenesis, modifying stem cell niche parameters, tissue engineering, the modulation of the inflammatory cells, and the application of stimulatory factors.

Cite this article: Bone Joint Res 2022;11(8):561–574.

1. Twenty cases of tarso-metatarsal joint injury have been studied with regard to the mechanism of injury, and experiments have been done on cadavers to confirm clinical impressions. 2. Injuries of the tarso-metatarsal joints occur by direct and indirect mechanisms, the latter being more common. 3. Indirect injuries occur in at least two ways-namely, acute abduction of the forefoot and plantar-flexion of the forefoot. 4. Most of the indirect injuries occur when the ankle joint is in a plantar-flexed position. 5. Whereas this foot injury once gained prominence on the field of battle amongst cavalrymen, it is currently associated with the motor car, the step ladder, the toboggan, the joy-rider, and commonly the simple misguided step

We describe the influence of the angle of immobilisation during partial weight-bearing on the forces across the extensor mechanism of the knee. Gait analysis was performed on eight healthy male subjects with the right knee in an orthotic brace locked at 0°, 10°, 20° and 30°, with the brace unlocked and also without a brace. The ground reaction force, the angle of the knee and the net external flexion movement about the knee were measured and the extensor mechanism force was calculated. The results showed a direct non-linear relationship between the angle of knee flexion and the extensor mechanism force. When a brace was applied, the lowest forces occurred when the brace was locked at 0°. At 30° the forces approached the failure strength of some fixation devices. We recommend that for potentially unstable injuries of the extensor mechanism, when mobilising with partial weight-bearing, the knee should be flexed at no more than 10°

Aims

The involvement of cyclin D1 in the proliferation of microglia, and the generation and maintenance of bone cancer pain (BCP), have not yet been clarified. We investigated the expression of microglia and cyclin D1, and the influences of cyclin D1 on pain threshold.

Six mechanisms which may produce fracture-separation of the proximal humeral epiphysis are proposed. Four of them are illustrated by case reports. It is suggested that they may be differentiated by examination of the patient and study of the radiographs. In unstable fractures manipulation is indicated and, if performed with an understanding of the mechanism of injury, will produce a stable reduction

A consecutive series of 150 patients with clavicular fractures is presented. In 81% detailed information regarding the mechanism of the injury was available and, of these, 94% had fractured their clavicle from a direct blow on the shoulder; only 6% had fallen on the outstretched hand. This finding, at variance with commonly held views regarding the mechanism of this injury, was further investigated by biomechanical analysis of the forces involved in clavicular fractures. The biomechanical model supported the clinical findings

1 . The concept of the capsular mechanism of the shoulder joint with regard to recurrent anterior dislocation of the shoulder has been defined and a survey of the literature presented. 2. An anatomical, including an embryological, investigation of shoulder joints with special reference to the structure and function of the glenoid labrum and to the variations in the arrangement of the gleno-humeral ligaments and the synovial recesses of the anterior capsular mechanism is reported. The labrum, which is generally believed to be a consistent, fibrocartilaginous structure, is shown to be a redundant portion of capsular tissue and a continuation of the capsule as it attaches to the osseous glenoid rim. The fibrocartilaginous element is confined to a small transition zone at the capsular attachment in the great majority of cases. The great variability in the arrangement of the gleno-humeral ligaments and synovial recesses is stressed, and it is shown that an anterior pouch of variable size is present when the middle gleno-humeral ligament is attached to the scapular neck and not to the labrum. 3. The basic lesions of the anterior capsular mechanism found at operation for recurrent anterior dislocation of the shoulder in twenty-five consecutive cases using a modified Bankart procedure with a standard anterior approach to the joint are reported, and the findings are correlated with the results of the anatomical investigation. In most cases the lesions were found to be of the Bankart type with or without avulsion of the periosteum of the scapular neck. In four cases, however, the soft-tissue attachment to the anterior glenoid rim was intact; in those cases a large synovial pouch was present and the middle gleno-humeral ligament was either not discernible or it arose from the scapular neck. In all cases a postero-lateral notch on the humeral head was palpable and laxity of the subscapularis could be demonstrated. When measured, the joint capacity was always greatly augmented. 4. The present work shows, from a basic standpoint, that Bankart's original idea that the recurrent state was due to the failure of healing of the fractured fibrocartilaginous glenoid labrum is no longer tenable. 5. Finally, the anomalous attachment or the insufficient development of the middle gleno-humeral ligament in certain cases of recurrent anterior shoulder dislocation is shown to provide the anatomical basis for the recurrent state in these cases; this is the weak area in the antero-inferior part of the capsule which has been described in the literature for the past hundred years. Thus we have returned to the original view of Hippocrates

We present the histological findings of an extensor mechanism allograft which was used in a total knee arthroplasty two years after implantation. Analysis of the graft was undertaken at four distinct anatomical levels and it was found to be incorporated into host tissue at each level. A wedge of fibrinoid necrosis, probably related to impingement of the graft on the tibial polyethylene insert, was seen. Impingement may play a role in the injury and necrosis of an allograft and may be one mode of failure in an extensor mechanism allograft

We measured the contact areas and contact stresses at the post-cam mechanism of a posterior-stabilised total knee arthroplasty when a posterior force of 500 N was applied to the Kirschner Performance, Scorpio Superflex, NexGen LPS Flex Fixed, and NexGen LPS Flex Mobile knee systems. Measurements were made at 90°, 120°, and 150° of flexion both in neutral rotation and 10° of internal rotation of the tibial component. Peak contact stresses at 90°, 120°, and 150° were 24.0, 33.9, and 28.8 MPa, respectively, for the Kirschner; 26.0, 32.4, and 22.1 MPa, respectively, for the Scorpio; and 34.1, 31.5, and 32.5 MPa, respectively, for the NexGen LPS Flex Fixed. With an internally rotated tibia, the contact stress increased significantly with all the fixed-bearing arthroplasties but not with the NexGen LPS Flex Mobile arthroplasty. The post-cam design should be modified in order to provide a larger contact area whilst avoiding any impingement and edge loading

The mechanism of the pivot shift was investigated by analysing movements under valgus torque in 29 fresh cadaveric knees. The movements were measured in three dimensions, using biplanar photography, when all the ligaments were intact, and then after the ligaments were sequentially divided. When only the anterior cruciate ligament was sectioned, the pivot shift occurred in seven out of 20 knees examined. In the other 13, though the pivot shift was not observed, an abnormal internal rotation occurred at between 10 degrees and 50 degrees of flexion. Division of the iliotibial tract in addition to division of the anterior cruciate ligament stopped the pivot shift, as the tibia remained internally rotated throughout the range of flexion. The axis of rotation of the pivot shift was located at the medial collateral ligament, which was kept tight by the applied valgus torque. The sudden movement in the pivot shift was caused by a complex interaction between the geometry of the knee and the valgus torque applied

We developed an in vivo model of the attachment of a patellar tendon to a metal implant to simulate the reconstruction of an extensor mechanism after replacement of the proximal tibia. In 24 ewes, the patellar tendon was attached to a hydroxyapatite (HA)-coated titanium prosthesis. In 12, the interface was augmented with autograft containing cancellous bone and marrow. In the remaining ewes, the interface was not grafted. Kinematic gait analysis showed nearly normal function of the joint by 12 weeks. Force-plate assessment showed a significant increase in functional weight-bearing in the grafted animals (p = 0.043). The tendon-implant interface showed that without graft, encapsulation of fibrous tissue occurred. With autograft, a developing tendon-bone-HA-implant interface was observed at six weeks and by 12 weeks a layered tendon-fibrocartilage-bone interface was seen which was similar to a direct-type enthesis. With stable mechanical fixation, an appropriate bioactive surface and biological augmentation the development of a functional tendon-implant interface can be achieved

This study reports the clinical outcome of reconstruction of deficient abductor muscles following revision total hip arthroplasty (THA), using a fresh–frozen allograft of the extensor mechanism of the knee. A retrospective analysis was conducted of 11 consecutive patients with a severe limp because of abductor deficiency which was confirmed on MRI scans. The mean age of the patients (three men and eight women) was 66.7 years (52 to 84), with a mean follow-up of 33 months (24 to 41). . Following surgery, two patients had no limp, seven had a mild limp, and two had a persistent severe limp (p = 0.004). The mean power of the abductors improved on the Medical Research Council scale from 2.15 to 3.8 (p < 0.001). Pre-operatively, all patients required a stick or walking frame; post-operatively, four patients were able to walk without an aid. Overall, nine patients had severe or moderate pain pre-operatively; ten patients had no or mild pain post-operatively. . At final review, the Harris hip score was good in five patients, fair in two and poor in four. . We conclude that using an extensor mechanism allograft is relatively effective in the treatment of chronic abductor deficiency of the hip after THA when techniques such as local tissue transfer are not possible. . Longer-term follow-up is necessary before the technique can be broadly applied. Cite this article: Bone Joint J 2015;97-B:1050–5

Objectives. The aim of this study was to investigate the effect of granulocyte-colony stimulating factor (G-CSF) on mesenchymal stem cell (MSC) proliferation in vitro and to determine whether pre-microfracture systemic administration of G-CSF (a bone marrow stimulant) could improve the quality of repaired tissue of a full-thickness cartilage defect in a rabbit model. Methods. MSCs from rabbits were cultured in a control medium and medium with G-CSF (low-dose: 4 μg, high-dose: 40 μg). At one, three, and five days after culturing, cells were counted. Differential potential of cultured cells were examined by stimulating them with a osteogenic, adipogenic and chondrogenic medium. A total of 30 rabbits were divided into three groups. The low-dose group (n = 10) received 10 μg/kg of G-CSF daily, the high-dose group (n = 10) received 50 μg/kg daily by subcutaneous injection for three days prior to creating cartilage defects. The control group (n = 10) was administered saline for three days. At 48 hours after the first injection, a 5.2 mm diameter cylindrical osteochondral defect was created in the femoral trochlea. At four and 12 weeks post-operatively, repaired tissue was evaluated macroscopically and microscopically. Results. The cell count in the low-dose G-CSF medium was significantly higher than that in the control medium. The differentiation potential of MSCs was preserved after culturing them with G-CSF. Macroscopically, defects were filled and surfaces were smoother in the G-CSF groups than in the control group at four weeks. At 12 weeks, the quality of repaired cartilage improved further, and defects were almost completely filled in all groups. Microscopically, at four weeks, defects were partially filled with hyaline-like cartilage in the G-CSF groups. At 12 weeks, defects were repaired with hyaline-like cartilage in all groups. Conclusions. G-CSF promoted proliferation of MSCs in vitro. The systemic administration of G-CSF promoted the repair of damaged cartilage possibly through increasing the number of MSCs in a rabbit model. Cite this article: T. Sasaki, R. Akagi, Y. Akatsu, T. Fukawa, H. Hoshi, Y. Yamamoto, T. Enomoto, Y. Sato, R. Nakagawa, K. Takahashi, S. Yamaguchi, T. Sasho. The effect of systemic administration of G-CSF on a full-thickness cartilage defect in a rabbit model MSC proliferation as presumed mechanism: G-CSF for cartilage repair. Bone Joint Res 2017;6:123–131. DOI: 10.1302/2046-3758.63.BJR-2016-0083

By polarising microscope and x-ray crystallographic techniques the annulus fibrosus has been shown to consist of regularly oriented sheets of collagen fibres. These results have been interpreted in terms of an elastic mechanism whereby thrust from the nucleus causes increased girth in the annulus. It is suggested that this is accomplished by a change in the angle between the axis of the fibres in adjacent uniaxial layers of the annulus. Furthermore, the loss of elasticity of the intervertebral disc associated with age would seem to be mainly due to changes occurring in the nucleus pulposus

1. An experimental study of the healing mechanism in circumscribed defects in femora of albino rats of the Wistar strain is described. 2. Only the outer one-fifth of the defect is repaired by subperiosteal bony callus, the rest of the defect being repaired by endosteal callus. 3. Subperiosteal callus does not bridge the defect until endosteal callus is developed fully. 4. As peripheral callus matures the greater part of the endosteal callus is resorbed, with the exception of trabeculae attached to the margin of the defect. 5. The resorbed area in the medullary part of the defect is gradually obliterated by deposition of inner circumferential lamellae. 6. There appear to be differences between the mechanism responsible for repair of fractures of a long bone and that which heals circumscribed bone defects

Studies derived from analyses of radiographs and dissections of cadaveric wrists have been directed at testing and disproving the commonly held theories that link chip fractures of the os triquetrum with avulsion. The authors found that the mechanism of such injuries involved a chisel action of the ulnar styloid upon the dorsum of the os triquetrum; furthermore, the impact of a fall on the outstretched arm with the hand rigidly held in strong dorsiflexion and ulnar deviation could be forceful enough to fracture the body of the os triquetrum as well. In all cases a striking prolongation of the ulnar styloid, beyond the surface of the ulnar head, was consistently noted

1. The semilunar cartilages are part of the rotator mechanism of the knee joint. 2. Movement of the weight-bearing knee comprises synchronous lateral rotation of the tibia with extension and medial rotation of the tibia with flexion. 3. When this synchrony is disturbed, injuries to the semilunar cartilages result. 4. Damage to the anterior two-thirds of the medial cartilage blocks lateral rotation of the tibia, with consequent physical signs that are pathognomonic of the retracted and the bowstring cartilage, which are the most common types of injury. 5. Each type of cartilage injury produces its own pattern of erosion of articular cartilage and its own sequence of symptoms as so-called arthritis develops. 6. The sequence of symptoms may be halted and often reversed by removal of the torn cartilage. Operation is warranted in most cases however long the history and whatever the age of the patient. 7. The development of medial retropatellar arthritis is explained. The symptoms are often relieved by removal of the medial semilunar cartilage and adequate post-operative rehabilitation

Recent surveys have shown that idiopathic structural scoliosis of mild degree is generally not progressive. We will propose a mechanism which may be responsible for deterioration in the few. It has been observed that the spinal cord, although displaced towards the concavity, does not rotate in company with the vertebrae, thus exposing the emerging nerve roots to the effects of traction and possibly of entrapment. We suggest that progression occurs when the neuraxis is unable to adjust to the change in the anatomy of vertebral column. Our proposition is based upon our findings in a complete spinal column obtained from a baby with structural scoliosis. Support is provided by intercostal angiography, and by observations upon normal anatomy, the pathological anatomy of mature scoliotic spines and the anatomy of contrived scoliosis in normal spines. Although our histological and electrophysiological investigations are incomplete we can demonstrate a significant increase in degenerate cells in the dorsal root ganglia at the apex on the convex side. Lack of suitable necropsy material prevents us from confirming our observations so that our report is inevitably preliminary. We enter a plea that careful examination of the neuraxis be undertaken whenever a specimen of a scoliotic spine becomes available

Experience with thirty-eight Asian children and adolescents who presented with either stiffness of the knee, genu recurvatum, habitual dislocation of the patella or congenital lateral dislocation of the patella showed that all those disorders were manifestations of contracture of the extensor mechanism, which fell into two groups according to the components involved. In Group I the main components affected were in the midline of the limb, namely rectus femoris and vastus intermedius; these patients presented with varying degrees of stiffness of the knee, or worse, with genu recurvatum. In Group II the main components involved were lateral to the midline of the limb, namely vastus lateralis and the ilio-tibial band; these patients presented with habitual dislocation of the patella, or worse, congenital lateral dislocation of the patella. In both groups untreated patients developed secondary adaptive changes such as subluxation of the tibia or marked genu valgum which made operative procedures more formidable and less effective. Release of the contracture should therefore be performed as early as possible

The factors involved in the mechanism leading to traumatic posterior dislocation of the hip are examined. In 47 adult patients who had previously suffered such a dislocation, ultrasound scans were used to measure femoral anteversion on both the affected and the uninjured side. In 36 normal adult volunteers, used as controls, similar measurements were made. Femoral anteversion on both the injured and uninjured side was significantly reduced in the patients compared with the volunteers. These findings are discussed in the light of previous work which indicates that medial rotation is a factor in the mechanism of posterior dislocation of the hip. It is suggested that reduced anteversion acts like medial rotation to make the hip more susceptible to posterior dislocation, and that the less the anteversion the more likely is the injury to be a dislocation rather than a fracture-dislocation. It is concluded that patients who suffer such dislocated hips belong at one extreme of the normal population, having either reduced femoral anteversion or even retroversion, and that this anatomical feature selects towards hip dislocation rather than to injury of the femoral shaft, knee or tibia during the appropriate type of accident

The aim of this study was to analyse the gait pattern, muscle force and functional outcome of patients who had undergone replacement of the proximal tibia for tumour and alloplastic reconstruction of the extensor mechanism using the patellar-loop technique. Between February 1998 and December 2009, we carried out wide local excision of a primary sarcoma of the proximal tibia, proximal tibial replacement and reconstruction of the extensor mechanism using the patellar-loop technique in 18 patients. Of these, nine were available for evaluation after a mean of 11.6 years (0.5 to 21.6). The strength of the knee extensors was measured using an Isobex machine and gait analysis was undertaken in our gait assessment laboratory. Functional outcome was assessed using the American Knee Society (AKS) and Musculoskeletal Tumor Society (MSTS) scores. The gait pattern of the patients differed in ground contact time, flexion heel strike, maximal flexion loading response and total sagittal plane excursion. The mean maximum active flexion was 91° (30° to 110°). The overall mean extensor lag was 1° (0° to 5°). The mean extensor muscle strength was 25.8% (8.3% to 90.3%) of that in the non-operated leg (p < 0.001). The mean functional scores were 68.7% (43.4% to 83.3%) (MSTS) and 71.1 (30 to 90) (AKS functional score). In summary, the results show that reconstruction of the extensor mechanism using this technique gives good biomechanical and functional results. The patients’ gait pattern is close to normal, except for a somewhat stiff knee gait pattern. The strength of the extensor mechanism is reduced, but sufficient for walking. . Cite this article: Bone Joint J 2015;97-B:1063–9

1. The claw position of a finger with intrinsic paralysis is caused by the blocking effect of the transverse lamina on the long extensor. This starts as soon as the metacarpo-phalangeal joint is hyperextended, and increases with further hyperextension. Thus the long extensor loses its pull on the interphalangeal joints and allows them to flex. Therefore, in intrinsic paralysis the claw position can be prevented or cured by keeping the metacarpo-phalangeal joint in flexion, however slight, which can be done by splinting, by tenodesis or by capsulorrhaphy.

2. Replacement of the intrinsics by some active element, although it may improve the action of the fingers, is not necessary for the correction of claw finger. The function of the intrinsics in the prevention of claw finger is not to be found in their extending effect on the interphalangeal joints, but in the flexion effect on the metacarpo-phalangeal joint, or at least in preventing its hyperextension. This is in accordance with the fact that loss of intrinsic function is disastrous only in supple fingers, in which the metacarpo-phalangeal joints tend to assume extreme degrees of hyperextension (Riordan 1953, Brand 1958). In such fingers, the wide range of hyperextension available at the metacarpo-phalangeal joints is, of course, part of a generalised laxity of the soft parts of the fingers. These soft parts generally tend to counteract the tendency to clawing; the less their resistance, the more the human finger as a whole will tend to behave like a musculo-articular model, and such a model without intrinsics will always immediately assume the claw position.

Segmental spinal reflexes (stretch reflexes) were studied in patients with scoliosis. The proprioceptive responses to the phasic stretch of the paraspinal muscles were asymmetric in all patients, and were increased on the convex side. The asymmetry was more pronounced when the patients were standing. The observed asymmetry of the reflex responses was taken to indicate asymmetry in the tone and postural activity of the superficial layer of the paraspinal muscles. A reciprocal relationship was found in the segmental reflex organisation between the superficial and deep layers of the paraspinal muscles. The increase in reflex response of the superficial muscles on the convex side can be due to diminished reciprocal inhibition from weak, deep muscles. Thus a segmental neurogenic disorder involving predominantly the deep paraspinal muscles of the convexity of the curve may be the primary lesion responsible for the development of scoliosis.

Many knee surgeons flex the knee and sometimes also extend the hip before inflating a tourniquet on the thigh. This practice stems from the belief that these manoeuvres prevent excessive strain on the quadriceps during surgery, the assumption being that movement of the muscle is restricted by an inflated tourniquet. We therefore examined, using ultrasound, the movement of the quadriceps muscle above and below the tourniquet before and after inflation.

We applied a tourniquet of standard size to the thigh of five volunteers for approximately five minutes. A bubble of air was injected into the quadriceps muscle above the tourniquet and was the proximal point of reference. The musculotendinous junction was the distal point. The movement of the reference point was measured by ultrasound before and after inflation of the tourniquet. Each measurement was repeated with either the knee flexed and the hip extended, or the hip flexed and the knee extended. The mean and standard deviation were recorded.

Before inflation the mean amount of passive movement was 1.1 ± 0.13 cm proximal and 4.0 ± 0.08 cm distal to the tourniquet, with a range of movement of the knee of 0° to 137° (6.7°). After inflation the mean passive movement was 1.0 ± 0.07 cm proximal and 4.0 ± 0.08 cm distal to the tourniquet with a range of 0° to 132° (± 7.6°).

The ultrasound findings therefore have shown no evidence of restriction of the quadriceps muscle by an inflated tourniquet.

1. A clinical test of diagnostic significance in Morton's metatarsalgia is described.

2. Findings at operation in twelve cases are recorded.

3. The causation of the digital neuroma is discussed.

A case of cervical traumatic paraplegia is described in which there was no evidence of damage to vertebrae, discs or ligaments. Experimental evidence suggests that such injuries may be caused by inward bulging of the ligamentum flavum during hyperextension. The reasons why this inward bulging may occur, despite the elasticity of the ligamentum flavum, are discussed. Treatment of such cases is considered and the importance of avoiding extension emphasised.

We used an in vivo model to assess the use of an autogenous cancellous bone block and marrow graft for augmenting tendon reattachment to metallic implants. We hypothesised that augmentation of the tendon-implant interface with a bone block would enable retention of the graft on the implant surface, enhance biological integration, and result in more consistent functional outcomes compared with previously reported morcellised graft augmentation techniques.

A significant improvement in functional weight-bearing was observed between six and 12 weeks. The significant increase in ground reaction force through the operated limb between six and 12 weeks was greater than that reported previously with morcellised graft augmented reconstructions. Histological appearance and collagen fibre orientation with bone block augmentation more closely resembled that of an intact enthesis compared with the morcellised grafting technique. Bone block augmentation of tendon-implant interfaces results in more reliable functional and histological outcomes, with a return to pre-operative levels of weight-bearing by 24 weeks.

Aims. Isolated acetabular liner exchange with a highly crosslinked polyethylene (HXLPE) component is an option to address polyethylene wear and osteolysis following total hip arthroplasty (THA) in the presence of a well-fixed acetabular shell. The liner can be fixed either with the original locking mechanism or by being cemented within the acetabular component. Whether the method used for fixation of the HXLPE liner has any bearing on the long-term outcomes is still unclear. Methods. Data were retrieved for all patients who underwent isolated acetabular component liner exchange surgery with a HXLPE component in our institute between August 2000 and January 2015. Patients were classified according to the fixation method used (original locking mechanism (n = 36) or cemented (n = 50)). Survival and revision rates were compared. A total of 86 revisions were performed and the mean duration of follow-up was 13 years. Results. A total of 20 patients (23.3%) had complications, with dislocation alone being the most common (8.1%; 7/86). Ten patients (11.6%) required re-revision surgery. Cementing the HXLPE liner (8.0%; 4/50) had a higher incidence of re-revision due to acetabular component liner-related complications than using the original locking mechanism (0%; 0/36; p = 0.082). Fixation using the original locking mechanism was associated with re-revision due to acetabular component loosening (8.3%; 3/36), compared to cementing (0%; 0/50; p = 0.038). Overall estimated mean survival was 19.2 years. There was no significant difference in the re-revision rate between the original locking mechanism (11.1%; 4/36) and cementing (12.0%; 6/50; p = 0.899). Using Kaplan-Meier survival analysis, the revision-free survival of HXLPE fixed with the original locking mechanism and cementing was 94.1% and 93.2%, respectively, at ten years, and 84.7% and 81.3%, respectively, at 20 years (p = 0.840). Conclusion. The re-revision rate and the revision-free survival following acetabular component liner exchange revision surgery using the HXLPE liner were not influenced by the fixation technique used. Both techniques were associated with good survival at a mean follow-up of 13 years. Careful patient selection is necessary for isolated acetabular component liner exchange revision surgery in order to achieve the best outcomes. Cite this article: Bone Joint J 2024;106-B(5 Supple B):59–65

Aims. To explore the novel molecular mechanisms of histone deacetylase 4 (HDAC4) in chondrocytes via RNA sequencing (RNA-seq) analysis. Methods. Empty adenovirus (EP) and a HDAC4 overexpression adenovirus were transfected into cultured human chondrocytes. The cell survival rate was examined by real-time cell analysis (RTCA) and EdU and flow cytometry assays. Cell biofunction was detected by Western blotting. The expression profiles of messenger RNAs (mRNAs) in the EP and HDAC4 transfection groups were assessed using whole-transcriptome sequencing (RNA-seq). Volcano plot, Gene Ontology, and pathway analyses were performed to identify differentially expressed genes (DEGs). For verification of the results, the A289E/S246/467/632 A sites of HDAC4 were mutated to enhance the function of HDAC4 by increasing HDAC4 expression in the nucleus. RNA-seq was performed to identify the molecular mechanism of HDAC4 in chondrocytes. Finally, the top ten DEGs associated with ribosomes were verified by quantitative polymerase chain reaction (QPCR) in chondrocytes, and the top gene was verified both in vitro and in vivo. Results. HDAC4 markedly improved the survival rate and biofunction of chondrocytes. RNA-seq analysis of the EP and HDAC4 groups showed that HDAC4 induced 2,668 significant gene expression changes in chondrocytes (1,483 genes upregulated and 1,185 genes downregulated, p < 0.05), and ribosomes exhibited especially large increases. The results were confirmed by RNA-seq of the EP versus mutated HDAC4 groups and the validations in vitro and in vivo. Conclusion. The enhanced ribosome pathway plays a key role in the mechanism by which HDAC4 improves the survival rate and biofunction of chondrocytes. Cite this article: Bone Joint Res 2023;12(7):433–446

Periprosthetic joint infection (PJI) is a difficult complication requiring a comprehensive eradication protocol. Cure rates have essentially stalled in the last two decades, using methods of antimicrobial cement joint spacers and parenteral antimicrobial agents. Functional spacers with higher-dose antimicrobial-loaded cement and antimicrobial-loaded calcium sulphate beads have emphasized local antimicrobial delivery on the premise that high-dose local antimicrobial delivery will enhance eradication. However, with increasing antimicrobial pressures, microbiota have responded with adaptive mechanisms beyond traditional antimicrobial resistance genes. In this review we describe adaptive resistance mechanisms that are relevant to the treatment of PJI. Some mechanisms are well known, but others are new. The objective of this review is to inform clinicians of the known adaptive resistance mechanisms of microbes relevant to PJI. We also discuss the implications of these adaptive mechanisms in the future treatment of PJI. Cite this article: Bone Joint J 2022;104-B(5):575–580

Aims. To investigate the effects of senescent osteocytes on bone homeostasis in the progress of age-related osteoporosis and explore the underlying mechanism. Methods. In a series of in vitro experiments, we used tert-Butyl hydroperoxide (TBHP) to induce senescence of MLO-Y4 cells successfully, and collected conditioned medium (CM) and senescent MLO-Y4 cell-derived exosomes, which were then applied to MC3T3-E1 cells, separately, to evaluate their effects on osteogenic differentiation. Furthermore, we identified differentially expressed microRNAs (miRNAs) between exosomes from senescent and normal MLO-Y4 cells by high-throughput RNA sequencing. Based on the key miRNAs that were discovered, the underlying mechanism by which senescent osteocytes regulate osteogenic differentiation was explored. Lastly, in the in vivo experiments, the effects of senescent MLO-Y4 cell-derived exosomes on age-related bone loss were evaluated in male SAMP6 mice, which excluded the effects of oestrogen, and the underlying mechanism was confirmed. Results. The CM and exosomes collected from senescent MLO-Y4 cells inhibited osteogenic differentiation of MC3T3-E1 cells. RNA sequencing detected significantly lower expression of miR-494-3p in senescent MLO-Y4 cell-derived exosomes compared with normal exosomes. The upregulation of exosomal miR-494-3p by miRNA mimics attenuated the effects of senescent MLO-Y4 cell-derived exosomes on osteogenic differentiation. Luciferase reporter assay demonstrated that miR-494-3p targeted phosphatase and tensin homolog (PTEN), which is a negative regulator of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Overexpression of PTEN or inhibition of the PI3K/AKT pathway blocked the functions of exosomal miR-494-3p. In SAMP6 mice, senescent MLO-Y4 cell-derived exosomes accelerated bone loss, which was rescued by upregulation of exosomal miR-494-3p. Conclusion. Reduced expression of miR-494-3p in senescent osteocyte-derived exosomes inhibits osteogenic differentiation and accelerates age-related bone loss via PTEN/PI3K/AKT pathway. Cite this article: Bone Joint Res 2024;13(2):52–65

Aims. Tibial tubercle osteotomy (TTO) facilitates surgical exposure and protects the extensor mechanism during revision total knee arthroplasty (rTKA). The purpose of this study was to determine the rates of bony union, complications, and reoperations following TTO during rTKA, to assess the functional outcomes of rTKA with TTO at two years’ minimum follow-up, and to identify the risk factors of failure. Methods. Between January 2010 and September 2020, 695 rTKAs were performed and data were entered into a prospective database. Inclusion criteria were rTKAs with concomitant TTO, without extensor mechanism allograft, and a minimum of two years’ follow-up. A total of 135 rTKAs were included, with a mean age of 65 years (SD 9.0) and a mean BMI of 29.8 kg/m. 2. (SD 5.7). The most frequent indications for revision were infection (50%; 68/135), aseptic loosening (25%; 34/135), and stiffness (13%; 18/135). Patients had standardized follow-up at six weeks, three months, six months, and annually thereafter. Complications and revisions were evaluated at the last follow-up. Functional outcomes were assessed using the Knee Society Score (KSS) and range of motion. Results. The mean follow-up was 51 months (SD 26; 24 to 121). Bony union was confirmed in 95% of patients (128/135) at a mean of 3.4 months (SD 2.7). The complication rate was 15% (20/135), consisting of nine tibial tubercle fracture displacements (6.7%), seven nonunions (5%), two delayed unions, one tibial fracture, and one wound dehiscence. Seven patients (5%) required eight revision procedures (6%): three bone grafts, three osteosyntheses, one extensor mechanism allograft, and one wound revision. The functional scores and flexion were significantly improved after surgery: mean KSS knee, 48.8 (SD 17) vs 79.6 (SD 20; p < 0.001); mean KSS function, 37.6 (SD 21) vs 70.2 (SD 30; p < 0.001); mean flexion, 81.5° (SD 33°) vs 93° (SD 29°; p = 0.004). Overall, 98% of patients (n = 132) had no extension deficit. The use of hinge implants was a significant risk factor for tibial tubercle fracture (p = 0.011). Conclusion. TTO during rTKA was an efficient procedure to improve knee exposure with a high union rate, but had significant specific complications. Functional outcomes were improved at mid term. Cite this article: Bone Joint J 2023;105-B(10):1078–1085

Aims. Currently, the effect of drug treatment for osteoporosis is relatively poor, and the side effects are numerous and serious. Melatonin is a potential drug to improve bone mass in postmenopausal women. Unfortunately, the mechanism by which melatonin improves bone metabolism remains unclear. The aim of this study was to further investigate the potential mechanism of melatonin in the treatment of osteoporosis. Methods. The effects of melatonin on mitochondrial apoptosis protein, bmal1 gene, and related pathway proteins of RAW264.7 (mouse mononuclear macrophage leukaemia cells) were analyzed by western blot. Cell Counting Kit-8 was used to evaluate the effect of melatonin on cell viability. Flow cytometry was used to evaluate the effect of melatonin on the apoptosis of RAW264.7 cells and mitochondrial membrane potential. A reactive oxygen species (ROS) detection kit was used to evaluate the level of ROS in osteoclast precursors. We used bmal1-small interfering RNAs (siRNAs) to downregulate the Bmal1 gene. We established a postmenopausal mouse model and verified the effect of melatonin on the bone mass of postmenopausal osteoporosis in mice via micro-CT. Bmal1 lentiviral activation particles were used to establish an in vitro model of overexpression of the bmal1 gene. Results. Melatonin promoted apoptosis of RAW264.7 cells and increased the expression of BMAL1 to inhibit the activation of ROS and phosphorylation of mitogen-activated protein kinase (MAPK)-p38. Silencing the bmal1 gene weakened the above effects of melatonin. After that, we used dehydrocorydaline (DHC) to enhance the activation of MAPK-p38, and the effects of melatonin on reducing ROS levels and promoting apoptosis of RAW264.7 cells were also blocked. Then, we constructed a mouse model of postmenopausal osteoporosis and administered melatonin. The results showed that melatonin improves bone loss in ovariectomized mice. Finally, we established a model of overexpression of the bmal1 gene, and these results suggest that the bmal1 gene can regulate ROS activity and change the level of the MAPK-p38 signalling pathway. Conclusion. Our study confirmed that melatonin promotes the apoptosis of RAW264.7 cells through BMAL1/ROS/MAPK-p38, and revealed the therapeutic effect and mechanism of melatonin in postmenopausal osteoporosis. This finding enriches BMAL1 as a potential target for the treatment of osteoporosis and the pathogenesis of postmenopausal osteoporosis. Cite this article: Bone Joint Res 2023;12(11):677–690

Aims. Distal third clavicle (DTC) fractures are increasing in incidence. Due to their instability and nonunion risk, they prove difficult to treat. Several different operative options for DTC fixation are reported but current evidence suggests variability in operative fixation. Given the lack of consensus, our objective was to determine the current epidemiological trends in DTC as well as their management within the UK. Methods. A multicentre retrospective cohort collaborative study was conducted. All patients over the age of 18 with an isolated DTC fracture in 2019 were included. Demographic variables were recorded: age; sex; side of injury; mechanism of injury; modified Neer classification grading; operative technique; fracture union; complications; and subsequent procedures. Baseline characteristics were described for demographic variables. Categorical variables were expressed as frequencies and percentages. Results. A total of 859 patients from 18 different NHS trusts (15 trauma units and three major trauma centres) were included. The mean age was 57 years (18 to 99). Overall, 56% of patients (n = 481) were male. The most common mechanisms of injury were simple fall (57%; n = 487) and high-energy fall (29%; n = 248); 87% (n = 748) were treated conservatively and 54% (n = 463) were Neer type I fractures. Overall, 32% of fractures (n = 275) were type II (22% type IIa (n = 192); 10% type IIb (n = 83)). With regards to operative management, 89% of patients (n = 748) who underwent an operation were under the age of 60. The main fixation methods were: hook plate (n = 47); locking plate (n = 34); tightrope (n = 5); and locking plate and tight rope (n = 7). Conclusion. Our study is the largest epidemiological review of DTC fractures in the UK. It is also the first to review the practice of DTC fixation. Most fractures are being treated nonoperatively. However, younger patients, suffering a higher-energy mechanism of injury, are more likely to undergo surgery. Hook plates are the predominantly used fixation method followed by locking plate. The literature is sparse on the best method of fixation for optimal outcomes for these patients. To answer this, a pragmatic RCT to determine optimal fixation method is required. Cite this article: Bone Jt Open 2022;3(12):953–959

Aims. In this investigation, we administered oxidative stress to nucleus pulposus cells (NPCs), recognized DNA-damage-inducible transcript 4 (DDIT4) as a component in intervertebral disc degeneration (IVDD), and devised a hydrogel capable of conveying small interfering RNA (siRNA) to IVDD. Methods. An in vitro model for oxidative stress-induced injury in NPCs was developed to elucidate the mechanisms underlying the upregulation of DDIT4 expression, activation of the reactive oxygen species (ROS)-thioredoxin-interacting protein (TXNIP)-NLRP3 signalling pathway, and nucleus pulposus pyroptosis. Furthermore, the mechanism of action of small interfering DDIT4 (siDDIT4) on NPCs in vitro was validated. A triplex hydrogel named siDDIT4@G5-P-HA was created by adsorbing siDDIT4 onto fifth-generation polyamidoamine (PAMAM) dendrimer using van der Waals interactions, and then coating it with hyaluronic acid (HA). In addition, we established a rat puncture IVDD model to decipher the hydrogel’s mechanism in IVDD. Results. A correlation between DDIT4 expression levels and disc degeneration was shown with human nucleus pulposus and needle-punctured rat disc specimens. We confirmed that DDIT4 was responsible for activating the ROS-TXNIP-NLRP3 axis during oxidative stress-induced pyroptosis in rat nucleus pulposus in vitro. Mitochondria were damaged during oxidative stress, and DDIT4 contributed to mitochondrial damage and ROS production. In addition, siDDIT4@G5-P-HA hydrogels showed good delivery activity of siDDIT4 to NPCs. In vitro studies illustrated the potential of the siDDIT4@G5-P-HA hydrogel for alleviating IVDD in rats. Conclusion. DDIT4 is a key player in mediating pyroptosis and IVDD in NPCs through the ROS-TXNIP-NLRP3 axis. Additionally, siDDIT4@G5-P-HA hydrogel has been found to relieve IVDD in rats. Our research offers an innovative treatment option for IVDD. Cite this article: Bone Joint Res 2024;13(5):247–260

Aims. To describe the epidemiology of acetabular fractures including patient characteristics, injury mechanisms, fracture patterns, treatment, and mortality. Methods. We retrieved information from the Swedish Fracture Register (SFR) on all patients with acetabular fractures, of the native hip joint in the adult skeleton, sustained between 2014 and 2020. Study variables included patient age, sex, injury date, injury mechanism, fracture classification, treatment, and mortality. Results. In total, 2,132 patients with acetabular fractures from the SFR were included in the study. The majority of the patients were male (62%) and aged over 70 years old (62%). For patients aged > 70 years, the 30-day mortality was 8% and one-year mortality 24%. For patients aged ≤ 70 years, the 30-day mortality was 0.2% and one-year mortality 2%. Low-energy injuries (63%) and anterior wall fractures (20%) were most common. Treatment was most often non-surgical (75%). Conclusion. The majority of patients who sustain an acetabular fracture are elderly (> 70 years), of male sex, and the fracture most commonly occurs after a simple, low-energy fall. Non-surgical treatment is chosen in the majority of acetabular fracture patients. The one-year mortality for elderly patients with acetabular fracture is similar to the mortality after hip fracture, and a similar multidisciplinary approach to care for these patients should be considered. Cite this article: Bone Jt Open 2023;4(9):652–658

Aims. This study examined the relationship between obesity (OB) and osteoporosis (OP), aiming to identify shared genetic markers and molecular mechanisms to facilitate the development of therapies that target both conditions simultaneously. Methods. Using weighted gene co-expression network analysis (WGCNA), we analyzed datasets from the Gene Expression Omnibus (GEO) database to identify co-expressed gene modules in OB and OP. These modules underwent Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and protein-protein interaction analysis to discover Hub genes. Machine learning refined the gene selection, with further validation using additional datasets. Single-cell analysis emphasized specific cell subpopulations, and enzyme-linked immunosorbent assay (ELISA), protein blotting, and cellular staining were used to investigate key genes. Results. WGCNA revealed critical gene modules for OB and OP, identifying the Toll-like receptor (TLR) signalling pathway as a common factor. TLR2 was the most significant gene, with a pronounced expression in macrophages. Elevated TLR2 expression correlated with increased adipose accumulation, inflammation, and osteoclast differentiation, linking it to OP development. Conclusion. Our study underscores the pivotal role of TLR2 in connecting OP and OB. It highlights the influence of TLR2 in macrophages, driving both diseases through a pro-inflammatory mechanism. These insights propose TLR2 as a potential dual therapeutic target for treating OP and OB. Cite this article: Bone Joint Res 2024;13(10):573–587

Aims. Circular RNA (circRNA) is involved in the regulation of articular cartilage degeneration induced by inflammatory factors or oxidative stress. In a previous study, we found that the expression of circStrn3 was significantly reduced in chondrocytes of osteoarthritis (OA) patients and OA mice. Therefore, the aim of this paper was to explore the role and mechanism of circStrn3 in osteoarthritis. Methods. Minus RNA sequencing, fluorescence in situ hybridization, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of circStrn3 in human and mouse OA cartilage tissues and chondrocytes. Chondrocytes were then stimulated to secrete exosomal miR-9-5p by cyclic tensile strain. Intra-articular injection of exosomal miR-9-5p into the model induced by destabilized medial meniscus (DMM) surgery was conducted to alleviate OA progression. Results. Tensile strain could decrease the expression of circStrn3 in chondrocytes. CircStrn3 expression was significantly decreased in human and mouse OA cartilage tissues and chondrocytes. CircStrn3 could inhibit matrix metabolism of chondrocytes through competitively ‘sponging’ miRNA-9-5p targeting Kruppel-like factor 5 (KLF5), indicating that the decrease in circStrn3 might be a protective factor in mechanical instability-induced OA. The tensile strain stimulated chondrocytes to secrete exosomal miR-9-5p. Exosomes with high miR-9-5p expression from chondrocytes could inhibit osteoblast differentiation by targeting KLF5. Intra-articular injection of exosomal miR-9-5p alleviated the progression of OA induced by destabilized medial meniscus surgery in mice. Conclusion. Taken together, these results demonstrate that reduction of circStrn3 causes an increase in miR-9-5p, which acts as a protective factor in mechanical instability-induced OA, and provides a novel mechanism of communication among joint components and a potential application for the treatment of OA. Cite this article: Bone Joint Res 2023;12(1):33–45

Aims. Osteoarthritis (OA) is a common degenerative disease. PA28γ is a member of the 11S proteasome activator and is involved in the regulation of several important cellular processes, including cell proliferation, apoptosis, and inflammation. This study aimed to explore the role of PA28γ in the occurrence and development of OA and its potential mechanism. Methods. A total of 120 newborn male mice were employed for the isolation and culture of primary chondrocytes. OA-related indicators such as anabolism, catabolism, inflammation, and apoptosis were detected. Effects and related mechanisms of PA28γ in chondrocyte endoplasmic reticulum (ER) stress were studied using western blotting, real-time polymerase chain reaction (PCR), and immunofluorescence. The OA mouse model was established by destabilized medial meniscus (DMM) surgery, and adenovirus was injected into the knee cavity of 15 12-week-old male mice to reduce the expression of PA28γ. The degree of cartilage destruction was evaluated by haematoxylin and eosin (HE) staining, safranin O/fast green staining, toluidine blue staining, and immunohistochemistry. Results. We found that PA28γ knockdown in chondrocytes can effectively improve anabolism and catabolism and inhibit inflammation, apoptosis, and ER stress. Moreover, PA28γ knockdown affected the phosphorylation of IRE1α and the expression of TRAF2, thereby affecting the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signalling pathways, and finally affecting the inflammatory response of chondrocytes. In addition, we found that PA28γ knockdown can promote the phosphorylation of signal transducer and activator of transcription 3 (STAT3), thereby inhibiting ER stress in chondrocytes. The use of Stattic (an inhibitor of STAT3 phosphorylation) enhanced ER stress. In vivo, we found that PA28γ knockdown effectively reduced cartilage destruction in a mouse model of OA induced by the DMM surgery. Conclusion. PA28γ knockdown in chondrocytes can inhibit anabolic and catabolic dysregulation, inflammatory response, and apoptosis in OA. Moreover, PA28γ knockdown in chondrocytes can inhibit ER stress by promoting STAT3 phosphorylation. Cite this article: Bone Joint Res 2024;13(11):659–672

Aims. We aimed to develop a gene signature that predicts the occurrence of postmenopausal osteoporosis (PMOP) by studying its genetic mechanism. Methods. Five datasets were obtained from the Gene Expression Omnibus database. Unsupervised consensus cluster analysis was used to determine new PMOP subtypes. To determine the central genes and the core modules related to PMOP, the weighted gene co-expression network analysis (WCGNA) was applied. Gene Ontology enrichment analysis was used to explore the biological processes underlying key genes. Logistic regression univariate analysis was used to screen for statistically significant variables. Two algorithms were used to select important PMOP-related genes. A logistic regression model was used to construct the PMOP-related gene profile. The receiver operating characteristic area under the curve, Harrell’s concordance index, a calibration chart, and decision curve analysis were used to characterize PMOP-related genes. Then, quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify the expression of the PMOP-related genes in the gene signature. Results. We identified three PMOP-related subtypes and four core modules. The muscle system process, muscle contraction, and actin filament-based movement were more active in the hub genes. We obtained five feature genes related to PMOP. Our analysis verified that the gene signature had good predictive power and applicability. The outcomes of the GSE56815 cohort were found to be consistent with the results of the earlier studies. qRT-PCR results showed that RAB2A and FYCO1 were amplified in clinical samples. Conclusion. The PMOP-related gene signature we developed and verified can accurately predict the risk of PMOP in patients. These results can elucidate the molecular mechanism of RAB2A and FYCO1 underlying PMOP, and yield new and improved treatment strategies, ultimately helping PMOP monitoring. Cite this article: Bone Joint Res 2022;11(8):548–560

Aims. Due to the recent rapid expansion of scooter sharing companies, there has been a dramatic increase in the number of electric scooter (e-scooter) injuries. Our purpose was to conduct a systematic review to characterize the demographic characteristics, most common injuries, and management of patients injured from electric scooters. Methods. We searched PubMed, EMBASE, Scopus, and Web of Science databases using variations of the term “electric scooter”. We excluded studies conducted prior to 2015, studies with a population of less than 50, case reports, and studies not focused on electric scooters. Data were analyzed using t-tests and p-values < 0.05 were considered significant. Results. We studied 5,705 patients from 34 studies. The mean age was 33.3 years (SD 3.5), and 58.3% (n = 3,325) were male. The leading mechanism of injury was falling (n = 3,595, 74.4%). Injured patients were more likely to not wear a helmet (n = 2,114; 68.1%; p < 0.001). The most common type of injury incurred was bony injuries (n = 2,761, 39.2%), of which upper limb fractures dominated (n = 1,236, 44.8%). Head and neck injuries composed 22.2% (n = 1,565) of the reported injuries, including traumatic brain injuries (n = 455; 2.5%), lacerations/abrasions/contusions (n = 500; 7.1%), intracerebral brain haemorrhages (n = 131; 1.9%), and concussions (n = 255; 3.2%). Standard radiographs comprised most images (n = 2,153; 57.7%). Most patients were treated and released without admission (n = 2,895; 54.5%), and 17.2% (n = 911) of injured patients required surgery. Qualitative analyses of the cost of injury revealed that any intoxication was associated with higher billing costs. Conclusion. The leading injuries from e-scooters are upper limb fractures. Falling was the leading mechanism of injury, and most patients did not wear a helmet. Future research should focus on injury characterization, treatment, and cost. Cite this article: Bone Jt Open 2022;3(9):674–683

This review provides a concise outline of the advances made in the care of patients and to the quality of life after a traumatic spinal cord injury (SCI) over the last century. Despite these improvements reversal of the neurological injury is not yet possible. Instead, current treatment is limited to providing symptomatic relief, avoiding secondary insults and preventing additional sequelae. However, with an ever-advancing technology and deeper understanding of the damaged spinal cord, this appears increasingly conceivable. A brief synopsis of the most prominent challenges facing both clinicians and research scientists in developing functional treatments for a progressively complex injury are presented. Moreover, the multiple mechanisms by which damage propagates many months after the original injury requires a multifaceted approach to ameliorate the human spinal cord. We discuss potential methods to protect the spinal cord from damage, and to manipulate the inherent inhibition of the spinal cord to regeneration and repair. Although acute and chronic SCI share common final pathways resulting in cell death and neurological deficits, the underlying putative mechanisms of chronic SCI and the treatments are not covered in this review

Aims. Treatment for delayed wound healing resulting from peripheral vascular diseases and diabetic foot ulcers remains a challenge. A novel surgical technique named ‘tibial cortex transverse transport’ (TTT) has been developed for treating peripheral ischaemia, with encouraging clinical effects. However, its underlying mechanisms remain unclear. In the present study, we explored the potential biological mechanisms of TTT surgery using various techniques in a rat TTT animal model. Methods. A novel rat model of TTT was established with a designed external fixator, and effects on wound healing were investigated. Laser speckle perfusion imaging, vessel perfusion, histology, and immunohistochemistry were used to evaluate the wound healing processes. Results. Gross and histological examinations showed that TTT technique accelerated wound closure and enhanced the quality of the newly formed skin tissues. In the TTT group, haematoxylin and eosin (H&E) staining demonstrated a better epidermis and dermis recovery, while immunohistochemical staining showed that TTT technique promoted local collagen deposition. The TTT technique also benefited to angiogenesis and immunomodulation. In the TTT group, blood flow in the wound area was higher than that of other groups according to laser speckle imaging with more blood vessels observed. Enhanced neovascularization was seen in the TTT group with double immune-labelling of CD31 and α-Smooth Muscle Actin (α-SMA). The number of M2 macrophages at the wound site in the TTT group was also increased. Conclusion. The TTT technique accelerated wound healing through enhanced angiogenesis and immunomodulation. Cite this article: Bone Joint Res 2022;11(4):189–199

The October 2023 Sports Roundup. 360. looks at: Extensor mechanism disruption in the treatment of dislocated and multiligament knee injuries; Treatment of knee osteoarthritis with injection of stem cells; Corticosteroid injection plus exercise or exercise alone as adjuvants for patients with plantar fasciitis?; Generalized joint hypermobility and a second ACL injury?; The VISA-A ((sedentary) questionnaire for Achilles tendinopathy?

Recognized anatomic variations that lead to patella instability include patella alta and trochlea dysplasia. Lateralization of the extensor mechanism relative to the trochlea is often considered to be a contributing factor; however, controversy remains as to the degree this contributes to instability and how this should be measured. As the tibial tuberosity-trochlear groove (TT-TG) is one of most common imaging measurements to assess lateralization of the extensor mechanism, it is important to understand its strengths and weaknesses. Care needs to be taken while interpreting the TT-TG value as it is affected by many factors. Medializing tibial tubercle osteotomy is sometimes used to correct the TT-TG, but may not truly address the underlying anatomical problem. This review set out to determine whether the TT-TG distance sufficiently summarizes the pathoanatomy, and if this assists with planning of surgery in patellar instability. Cite this article: Bone Jt Open 2022;3(3):268–274

Osteoarthritis (OA) is mainly caused by ageing, strain, trauma, and congenital joint abnormalities, resulting in articular cartilage degeneration. During the pathogenesis of OA, the changes in subchondral bone (SB) are not only secondary manifestations of OA, but also an active part of the disease, and are closely associated with the severity of OA. In different stages of OA, there were microstructural changes in SB. Osteocytes, osteoblasts, and osteoclasts in SB are important in the pathogenesis of OA. The signal transduction mechanism in SB is necessary to maintain the balance of a stable phenotype, extracellular matrix (ECM) synthesis, and bone remodelling between articular cartilage and SB. An imbalance in signal transduction can lead to reduced cartilage quality and SB thickening, which leads to the progression of OA. By understanding changes in SB in OA, researchers are exploring drugs that can regulate these changes, which will help to provide new ideas for the treatment of OA. Cite this article: Bone Joint Res 2023;12(9):536–545

Periprosthetic joint infection represents a devastating complication after total elbow arthroplasty. Several measures can be implemented before, during, and after surgery to decrease infection rates, which exceed 5%. Debridement with antibiotics and implant retention has been reported to be successful in less than one-third of acute infections, but still plays a role. For elbows with well-fixed implants, staged retention seems to be equally successful as the more commonly performed two-stage reimplantation, both with a success rate of 70% to 80%. Permanent resection or even amputation are occasionally considered. Not uncommonly, a second-stage reimplantation requires complex reconstruction of the skeleton with allografts, and the extensor mechanism may also be deficient. Further developments are needed to improve our management of infection after elbow arthroplasty. Cite this article: Bone Joint J 2024;106-B(11):1321–1326

Aims. Gap junction intercellular communication (GJIC) in osteocytes is impaired by oxidative stress, which is associated with age-related bone loss. Ageing is accompanied by the accumulation of advanced oxidation protein products (AOPPs). However, it is still unknown whether AOPP accumulation is involved in the impairment of osteocytes’ GJIC. This study aims to investigate the effect of AOPP accumulation on osteocytes’ GJIC in aged male mice and its mechanism. Methods. Changes in AOPP levels, expression of connexin43 (Cx43), osteocyte network, and bone mass were detected in 18-month-old and three-month-old male mice. Cx43 expression, GJIC function, mitochondria membrane potential, reactive oxygen species (ROS) levels, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation were detected in murine osteocyte-like cells (MLOY4 cells) treated with AOPPs. The Cx43 expression, osteocyte network, bone mass, and mechanical properties were detected in three-month-old mice treated with AOPPs for 12 weeks. Results. The AOPP levels were increased in aged mice and correlated with degeneration of osteocyte network, loss of bone mass, and decreased Cx43 expression. AOPP intervention induced NADPH oxidase activation and mitochondrial dysfunction, triggered ROS generation, reduced Cx43 expression, and ultimately impaired osteocytes’ GJIC, which were ameliorated by NADPH oxidase inhibitor apocynin, mitochondria-targeted superoxide dismutase mimetic (mito-TEMPO), and ROS scavenger N-acetyl cysteine. Chronic AOPP loading accelerated the degradation of osteocyte networks and decreased Cx43 expression, resulting in deterioration of bone mass and mechanical properties in vivo. Conclusion. Our study suggests that AOPP accumulation contributes to age-related impairment of GJIC in osteocytes of male mice, which may be part of the pathogenic mechanism responsible for bone loss during ageing. Cite this article: Bone Joint Res 2022;11(7):413–425

Aims. This study aimed to explore the role of small colony variants (SCVs) of Staphylococcus aureus in intraosseous invasion and colonization in patients with periprosthetic joint infection (PJI). Methods. A PJI diagnosis was made according to the MusculoSkeletal Infection Society (MSIS) for PJI. Bone and tissue samples were collected intraoperatively and the intracellular invasion and intraosseous colonization were detected. Transcriptomics of PJI samples were analyzed and verified by polymerase chain reaction (PCR). Results. SCVs can be isolated from samples collected from chronic PJIs intraoperatively. Transmission electron microscopy (TEM) and immunofluorescence (IF) showed that there was more S. aureus in bone samples collected from chronic PJIs, but much less in bone samples from acute PJIs, providing a potential mechanism of PJI. Immunofluorescence results showed that SCVs of S. aureus were more likely to invade osteoblasts in vitro. Furthermore, TEM and IF also demonstrated that SCVs of S. aureus were more likely to invade and colonize in vivo. Cluster analysis and principal component analysis (PCA) showed that there were substantial differences in gene expression profiles between chronic and acute PJI. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these differentially expressed genes were enriched to chemokine-related signal pathways. PCR also verified these results. Conclusion. Our study has shown that the S. aureus SCVs have a greater ability to invade and colonize in bone, resulting in S. aureus remaining in bone tissues long-term, thus explaining the pathogenesis of chronic PJI. Cite this article: Bone Joint Res 2022;11(12):843–853

The critical relationship between airborne microbiological contamination in an operating theatre and surgical site infection (SSI) is well known. The aim of this annotation is to explain the scientific basis of using settle plates to audit the quality of air, and to provide information about the practicalities of using them for the purposes of clinical audit. The microbiological quality of the air in most guidance is defined by volumetric sampling, but this method is difficult for surgical departments to use on a routine basis. Settle plate sampling, which mimics the mechanism of deposition of airborne microbes onto open wounds and sterile instruments, is a good alternative method of assessing the quality of the air. Current practice is not to sample the air in an operating theatre during surgery, but to rely on testing the engineering systems which deliver the clean air. This is, however, not good practice and microbiological testing should be carried out routinely during operations as part of clinical audit. Cite this article: Bone Joint J 2024;106-B(9):887–891

Bone regeneration and repair are crucial to ambulation and quality of life. Factors such as poor general health, serious medical comorbidities, chronic inflammation, and ageing can lead to delayed healing and nonunion of fractures, and persistent bone defects. Bioengineering strategies to heal bone often involve grafting of autologous bone marrow aspirate concentrate (BMAC) or mesenchymal stem cells (MSCs) with biocompatible scaffolds. While BMAC shows promise, variability in its efficacy exists due to discrepancies in MSC concentration and robustness, and immune cell composition. Understanding the mechanisms by which macrophages and lymphocytes – the main cellular components in BMAC – interact with MSCs could suggest novel strategies to enhance bone healing. Macrophages are polarized into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, and influence cell metabolism and tissue regeneration via the secretion of cytokines and other factors. T cells, especially helper T1 (Th1) and Th17, promote inflammation and osteoclastogenesis, whereas Th2 and regulatory T (Treg) cells have anti-inflammatory pro-reconstructive effects, thereby supporting osteogenesis. Crosstalk among macrophages, T cells, and MSCs affects the bone microenvironment and regulates the local immune response. Manipulating the proportion and interactions of these cells presents an opportunity to alter the local regenerative capacity of bone, which potentially could enhance clinical outcomes. Cite this article: Bone Joint Res 2024;13(9):462–473

Aims. The metabolic variations between the cartilage of osteoarthritis (OA) and Kashin-Beck disease (KBD) remain largely unknown. Our study aimed to address this by conducting a comparative analysis of the metabolic profiles present in the cartilage of KBD and OA. Methods. Cartilage samples from patients with KBD (n = 10) and patients with OA (n = 10) were collected during total knee arthroplasty surgery. An untargeted metabolomics approach using liquid chromatography coupled with mass spectrometry (LC-MS) was conducted to investigate the metabolomics profiles of KBD and OA. LC-MS raw data files were converted into mzXML format and then processed by the XCMS, CAMERA, and metaX toolbox implemented with R software. The online Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to annotate the metabolites by matching the exact molecular mass data of samples with those from the database. Results. A total of 807 ion features were identified for KBD and OA, including 577 positive (240 for upregulated and 337 for downregulated) and 230 negative (107 for upregulated and 123 for downregulated) ions. After annotation, LC-MS identified significant expressions of ten upregulated and eight downregulated second-level metabolites, and 183 upregulated and 162 downregulated first-level metabolites between KBD and OA. We identified differentially expressed second-level metabolites that are highly associated with cartilage damage, including dimethyl sulfoxide, uric acid, and betaine. These metabolites exist in sulphur metabolism, purine metabolism, and glycine, serine, and threonine metabolism. Conclusion. This comprehensive comparative analysis of metabolism in OA and KBD cartilage provides new evidence of differences in the pathogenetic mechanisms underlying cartilage damage in these two conditions. Cite this article: Bone Joint Res 2024;13(7):362–371

Aims. This study was performed to explore the effect of melatonin on pyroptosis in nucleus pulposus cells (NPCs) and the underlying mechanism of that effect. Methods. This experiment included three patients diagnosed with lumbar disc herniation who failed conservative treatment. Nucleus pulposus tissue was isolated from these patients when they underwent surgical intervention, and primary NPCs were isolated and cultured. Western blotting, reverse transcription polymerase chain reaction, fluorescence staining, and other methods were used to detect changes in related signalling pathways and the ability of cells to resist pyroptosis. Results. Western blot analysis confirmed the expression of cleaved CASP-1 and melatonin receptor (MT-1A-R) in NPCs. The cultured NPCs were identified by detecting the expression of CD24, collagen type II, and aggrecan. After treatment with hydrogen peroxide, the pyroptosis-related proteins NLR family pyrin domain containing 3 (NLRP3), cleaved CASP-1, N-terminal fragment of gasdermin D (GSDMD-N), interleukin (IL)-18, and IL-1β in NPCs were upregulated, and the number of propidium iodide (PI)-positive cells was also increased, which was able to be alleviated by pretreatment with melatonin. The protective effect of melatonin on pyroptosis was blunted by both the melatonin receptor antagonist luzindole and the nuclear factor erythroid 2–related factor 2 (Nrf2) inhibitor ML385. In addition, the expression of the transcription factor Nrf2 was up- or downregulated when the melatonin receptor was activated or blocked by melatonin or luzindole, respectively. Conclusion. Melatonin protects NPCs against reactive oxygen species-induced pyroptosis by upregulating the transcription factor Nrf2 via melatonin receptors. Cite this article: Bone Joint Res 2023;12(3):202–211

Aims. Rheumatoid arthritis (RA) is a common chronic immune disease. Berberine, as its main active ingredient, was also contained in a variety of medicinal plants such as Berberaceae, Buttercup, and Rutaceae, which are widely used in digestive system diseases in traditional Chinese medicine with anti-inflammatory and antibacterial effects. The aims of this article were to explore the therapeutic effect and mechanism of berberine on rheumatoid arthritis. Methods. Cell Counting Kit-8 was used to evaluate the effect of berberine on the proliferation of RA fibroblast-like synoviocyte (RA-FLS) cells. The effect of berberine on matrix metalloproteinase (MMP)-1, MMP-3, receptor activator of nuclear factor kappa-Β ligand (RANKL), tumour necrosis factor alpha (TNF-α), and other factors was determined by enzyme-linked immunoassay (ELISA) kit. Transcriptome technology was used to screen related pathways and the potential targets after berberine treatment, which were verified by reverse transcription-polymerase chain reaction (RT-qPCR) and Western blot (WB) technology. Results. Berberine inhibited proliferation and adhesion of RA-FLS cells, and significantly reduced the expression of MMP-1, MMP-3, RANKL, and TNF-α. Transcriptional results suggested that berberine intervention mainly regulated forkhead box O (FOXO) signal pathway, prolactin signal pathway, neurotrophic factor signal pathway, and hypoxia-inducible factor 1 (HIF-1) signal pathway. Conclusion. The effect of berberine on RA was related to the regulation of RAS/mitogen-activated protein kinase/FOXO/HIF-1 signal pathway in RA-FLS cells. Cite this article: Bone Joint Res 2023;12(2):91–102

Aims. Osteoporosis is characterized by decreased trabecular bone volume, and microarchitectural deterioration in the medullary cavity. Interleukin-19 (IL-19), a member of the IL-10 family, is an anti-inflammatory cytokine produced primarily by macrophages. The aim of our study was to investigate the effect of IL-19 on osteoporosis. Methods. Blood and femoral bone marrow suspension IL-19 levels were first measured in the lipopolysaccharide (LPS)-induced bone loss model. Small interfering RNA (siRNA) was applied to knock down IL-19 for further validation. Thereafter, osteoclast production was stimulated with IL-19 in combination with mouse macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). The effect of IL-19 was subsequently evaluated using tartrate-resistant acid phosphatase (TRAP) staining and quantitative real-time polymerase chain reaction (RT-qPCR). The effect of IL-19 on osteoprotegerin (OPG) was then assessed using in vitro recombinant IL-19 treatment of primary osteoblasts and MLO-Y4 osteoblast cell line. Finally, transient transfection experiments and chromatin immunoprecipitation (ChIP) experiments were used to examine the exact mechanism of action. Results. In the LPS-induced bone loss mouse model, the levels of IL-19 in peripheral blood serum and femoral bone marrow suspension were significantly increased. The in vivo results indicated that global IL-19 deletion had no significant effect on RANKL content in the serum and bone marrow, but could increase the content of OPG in serum and femoral bone marrow, suggesting that IL-19 inhibits OPG expression in bone marrow mesenchymal stem cells (BMSCs) and thus increases bone resorption. Conclusion. IL-19 promotes bone resorption by suppressing OPG expression in BMSCs in a LPS-induced bone loss mouse model, which highlights the potential benefits and side effects of IL-19 for future clinical applications. Cite this article: Bone Joint Res 2023;12(11):691–701

Aims. This study aimed to investigate the role and mechanism of meniscal cell lysate (MCL) in fibroblast-like synoviocytes (FLSs) and osteoarthritis (OA). Methods. Meniscus and synovial tissue were collected from 14 patients with and without OA. MCL and FLS proteins were extracted and analyzed by liquid chromatography‒mass spectrometry (LC‒MS). The roles of MCL and adenine nucleotide translocase 3 (ANT3) in FLSs were examined by enzyme-linked immunosorbent assay (ELISA), flow cytometry, immunofluorescence, and transmission electron microscopy. Histological analysis was performed to determine ANT3 expression levels in a male mouse model. Results. We discovered for the first time that MCL was substantially enriched in the synovial fluid of OA patients and promoted the release of inflammatory cytokines from FLSs through MCL phagocytosis. Through LC‒MS, ANT3 was identified and determined to be significantly upregulated in MCL and OA-FLSs, corresponding to impaired mitochondrial function and cell viability in OA-FLSs. Mitochondrial homeostasis was restored by ANT3 suppression, thereby alleviating synovial inflammation. Furthermore, elevated ANT3 levels inhibited ERK phosphorylation. Specifically, silencing ANT3 prevented inhibition of ERK phosphorylation and significantly reduced the elevation of reactive oxygen species (ROS) and JC1 membrane potential in MCL-induced synovial inflammation. Conclusion. This study revealed the important roles of MCL and ANT3 in FLS mitochondria. Silencing ANT3 rescued ERK phosphorylation, thereby restoring mitochondrial homeostasis in FLSs and alleviating synovitis and OA development, offering a potential target for treating synovitis and preventing early-stage OA. Cite this article: Bone Joint Res 2023;12(4):274–284

Aims. This study explored the shared genetic traits and molecular interactions between postmenopausal osteoporosis (POMP) and sarcopenia, both of which substantially degrade elderly health and quality of life. We hypothesized that these motor system diseases overlap in pathophysiology and regulatory mechanisms. Methods. We analyzed microarray data from the Gene Expression Omnibus (GEO) database using weighted gene co-expression network analysis (WGCNA), machine learning, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to identify common genetic factors between POMP and sarcopenia. Further validation was done via differential gene expression in a new cohort. Single-cell analysis identified high expression cell subsets, with mononuclear macrophages in osteoporosis and muscle stem cells in sarcopenia, among others. A competitive endogenous RNA network suggested regulatory elements for these genes. Results. Signal transducer and activator of transcription 3 (STAT3) was notably expressed in both conditions. Single-cell analysis pinpointed specific cells with high STAT3 expression, and microRNA (miRNA)-125a-5p emerged as a potential regulator. Experiments confirmed the crucial role of STAT3 in osteoclast differentiation and muscle proliferation. Conclusion. STAT3 has emerged as a key gene in both POMP and sarcopenia. This insight positions STAT3 as a potential common therapeutic target, possibly improving management strategies for these age-related diseases. Cite this article: Bone Joint Res 2024;13(8):411–426

Aims. Degenerative cervical spondylosis (DCS) is a common musculoskeletal disease that encompasses a wide range of progressive degenerative changes and affects all components of the cervical spine. DCS imposes very large social and economic burdens. However, its genetic basis remains elusive. Methods. Predicted whole-blood and skeletal muscle gene expression and genome-wide association study (GWAS) data from a DCS database were integrated, and functional summary-based imputation (FUSION) software was used on the integrated data. A transcriptome-wide association study (TWAS) was conducted using FUSION software to assess the association between predicted gene expression and DCS risk. The TWAS-identified genes were verified via comparison with differentially expressed genes (DEGs) in DCS RNA expression profiles in the Gene Expression Omnibus (GEO) (Accession Number: GSE153761). The Functional Mapping and Annotation (FUMA) tool for genome-wide association studies and Meta tools were used for gene functional enrichment and annotation analysis. Results. The TWAS detected 420 DCS genes with p < 0.05 in skeletal muscle, such as ribosomal protein S15A (RPS15A) (PTWAS = 0.001), and 110 genes in whole blood, such as selectin L (SELL) (PTWAS = 0.001). Comparison with the DCS RNA expression profile identified 12 common genes, including Apelin Receptor (APLNR) (PTWAS = 0.001, PDEG = 0.025). In total, 148 DCS-enriched Gene Ontology (GO) terms were identified, such as mast cell degranulation (GO:0043303); 15 DCS-enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified, such as the sphingolipid signalling pathway (ko04071). Nine terms, such as degradation of the extracellular matrix (R-HSA-1474228), were common to the TWAS enrichment results and the RNA expression profile. Conclusion. Our results identify putative susceptibility genes; these findings provide new ideas for exploration of the genetic mechanism of DCS development and new targets for preclinical intervention and clinical treatment. Cite this article: Bone Joint Res 2023;12(1):80–90

Aims. Rotator cuff tear (RCT) is the leading cause of shoulder pain, primarily associated with age-related tendon degeneration. This study aimed to elucidate the potential differential gene expressions in tendons across different age groups, and to investigate their roles in tendon degeneration. Methods. Linear regression and differential expression (DE) analyses were performed on two transcriptome profiling datasets of torn supraspinatus tendons to identify age-related genes. Subsequent functional analyses were conducted on these candidate genes to explore their potential roles in tendon ageing. Additionally, a secondary DE analysis was performed on candidate genes by comparing their expressions between lesioned and normal tendons to explore their correlations with RCTs. Results. We identified 49 genes in torn supraspinatus tendons associated with advancing age. Among them, five age-related genes showed DE in lesioned tendons compared to normal tendons. Functional analyses and previous studies have highlighted their specific enrichments in biological functions, such as muscle development (e.g. myosin heavy chain 3 (MYH3)), transcription regulation (e.g. CCAAT enhancer binding brotein delta (CEBPD)), and metal ion homeostasis (e.g. metallothionein 1X (MT1X)). Conclusion. This study uncovered molecular aspects of tendon ageing and their potential links to RCT development, offering insights for targeted interventions. These findings enhance our understanding of the mechanisms of tendon degeneration, allowing potential strategies to be made for reducing the incidence of RCT. Cite this article: Bone Joint Res 2024;13(9):474–484

Aims. Frailty greatly increases the risk of adverse outcome of trauma in older people. Frailty detection tools appear to be unsuitable for use in traumatically injured older patients. We therefore aimed to develop a method for detecting frailty in older people sustaining trauma using routinely collected clinical data. Methods. We analyzed prospectively collected registry data from 2,108 patients aged ≥ 65 years who were admitted to a single major trauma centre over five years (1 October 2015 to 31 July 2020). We divided the sample equally into two, creating derivation and validation samples. In the derivation sample, we performed univariate analyses followed by multivariate regression, starting with 27 clinical variables in the registry to predict Clinical Frailty Scale (CFS; range 1 to 9) scores. Bland-Altman analyses were performed in the validation cohort to evaluate any biases between the Nottingham Trauma Frailty Index (NTFI) and the CFS. Results. In the derivation cohort, five of the 27 variables were strongly predictive of the CFS (regression coefficient B = 6.383 (95% confidence interval 5.03 to 7.74), p < 0.001): age, Abbreviated Mental Test score, admission haemoglobin concentration (g/l), pre-admission mobility (needs assistance or not), and mechanism of injury (falls from standing height). In the validation cohort, there was strong agreement between the NTFI and the CFS (mean difference 0.02) with no apparent systematic bias. Conclusion. We have developed a clinically applicable tool using easily and routinely measured physiological and functional parameters, which clinicians and researchers can use to guide patient care and to stratify the analysis of quality improvement and research projects. Cite this article: Bone Joint J 2024;106-B(4):412–418

Aims. Osteoarthritis (OA) is a prevalent joint disorder with inflammatory response and cartilage deterioration as its main features. Dihydrocaffeic acid (DHCA), a bioactive component extracted from natural plant (gynura bicolor), has demonstrated anti-inflammatory properties in various diseases. We aimed to explore the chondroprotective effect of DHCA on OA and its potential mechanism. Methods. In vitro, interleukin-1 beta (IL-1β) was used to establish the mice OA chondrocytes. Cell counting kit-8 evaluated chondrocyte viability. Western blotting analyzed the expression levels of collagen II, aggrecan, SOX9, inducible nitric oxide synthase (iNOS), IL-6, matrix metalloproteinases (MMPs: MMP1, MMP3, and MMP13), and signalling molecules associated with nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Immunofluorescence analysis assessed the expression of aggrecan, collagen II, MMP13, and p-P65. In vivo, a destabilized medial meniscus (DMM) surgery was used to induce mice OA knee joints. After injection of DHCA or a vehicle into the injured joints, histological staining gauged the severity of cartilage damage. Results. DHCA prevented iNOS and IL-6 from being upregulated by IL-1β. Moreover, the IL-1β-induced upregulation of MMPs could be inhibited by DHCA. Additionally, the administration of DHCA counteracted IL-1β-induced downregulation of aggrecan, collagen II, and SOX9. DHCA protected articular cartilage by blocking the NF-κB and MAPK pathways. Furthermore, DHCA mitigated the destruction of articular cartilage in vivo. Conclusion. We present evidence that DHCA alleviates inflammation and cartilage degradation in OA chondrocytes via suppressing the NF-κB and MAPK pathways, indicating that DHCA may be a potential agent for OA treatment. Cite this article: Bone Joint Res 2023;12(4):259–273

Aims. Long non-coding RNAs (lncRNAs) act as crucial regulators in osteoporosis (OP). Nonetheless, the effects and potential molecular mechanism of lncRNA PCBP1 Antisense RNA 1 (PCBP1-AS1) on OP remain largely unclear. The aim of this study was to explore the role of lncRNA PCBP1-AS1 in the pathogenesis of OP. Methods. Using quantitative real-time polymerase chain reaction (qRT-PCR), osteogenesis-related genes (alkaline phosphatase (ALP), osteocalcin (OCN), osteopontin (OPN), and Runt-related transcription factor 2 (RUNX2)), PCBP1-AS1, microRNA (miR)-126-5p, group I Pak family member p21-activated kinase 2 (PAK2), and their relative expression levels were determined. Western blotting was used to examine the expression of PAK2 protein. Cell Counting Kit-8 (CCK-8) assay was used to measure cell proliferation. To examine the osteogenic differentiation, Alizarin red along with ALP staining was used. RNA immunoprecipitation assay and bioinformatics analysis, as well as a dual-luciferase reporter, were used to study the association between PCBP1-AS1, PAK2, and miR-126-5p. Results. The expression of PCBP1-AS1 was pre-eminent in OP tissues and decreased throughout the development of human bone marrow-derived mesenchymal stem cells (hBMSCs) into osteoblasts. PCBP1-AS1 knockdown and overexpression respectively promoted and suppressed hBMSC proliferation and osteogenic differentiation capacity. Mechanistically, PCBP1-AS1 sponged miR-126-5p and consequently targeted PAK2. Inhibiting miR-126-5p significantly counteracted the beneficial effects of PCBP1-AS1 or PAK2 knockdown on hBMSCs’ ability to differentiate into osteoblasts. Conclusion. PCBP1-AS1 is responsible for the development of OP and promotes its progression by inducing PAK2 expression via competitively binding to miR-126-5p. PCBP1-AS1 may therefore be a new therapeutic target for OP patients. Cite this article: Bone Joint Res 2023;12(6):375–386

Aims. The primary aim of this study was to identify independent predictors associated with nonunion and delayed union of tibial diaphyseal fractures treated with intramedullary nailing. The secondary aim was to assess the Radiological Union Scale for Tibial fractures (RUST) score as an early predictor of tibial fracture nonunion. Methods. A consecutive series of 647 patients who underwent intramedullary nailing for tibial diaphyseal fractures were identified from a trauma database. Demographic data, comorbidities, smoking status, alcohol consumption, use of non-steroidal anti-inflammatory drugs (NSAIDs), and steroid use were documented. Details regarding mechanism of injury, fracture classification, complications, and further surgery were recorded. Nonunion was defined as the requirement for revision surgery to achieve union. Delayed union was defined as a RUST score < 10 at six months postoperatively. Results. There were 41 nonunions (6.3%), of which 13 were infected (31.7%), and 77 delayed unions (11.9%). There were 127 open fractures (19.6%). Adjusting for confounding variables, NSAID use (odds ratio (OR) 3.50; p = 0.042), superficial infection (OR 3.00; p = 0.026), open fractures (OR 5.44; p < 0.001), and high-energy mechanism (OR 2.51; p = 0.040) were independently associated with nonunion. Smoking (OR 1.76; p = 0.034), open fracture (OR 2.82; p = 0.001), and high-energy mechanism (OR 1.81; p = 0.030) were independent predictors associated with delayed union. The RUST score at six-week follow-up was highly predictive of nonunion (sensitivity and specificity of 75%). Conclusion. NSAID use, high-energy mechanisms, open fractures, and superficial infection were independently associated with nonunion in patients with tibial diaphyseal fractures treated with intramedullary nailing. The six-week RUST score may be useful in identifying patients at risk of nonunion. Cite this article: Bone Jt Open 2021;2(4):227–235

Aims. Lumbar spinal stenosis (LSS) is a common skeletal system disease that has been partly attributed to genetic variation. However, the correlation between genetic variation and pathological changes in LSS is insufficient, and it is difficult to provide a reference for the early diagnosis and treatment of the disease. Methods. We conducted a transcriptome-wide association study (TWAS) of spinal canal stenosis by integrating genome-wide association study summary statistics (including 661 cases and 178,065 controls) derived from Biobank Japan, and pre-computed gene expression weights of skeletal muscle and whole blood implemented in FUSION software. To verify the TWAS results, the candidate genes were furthered compared with messenger RNA (mRNA) expression profiles of LSS to screen for common genes. Finally, Metascape software was used to perform enrichment analysis of the candidate genes and common genes. Results. TWAS identified 295 genes with permutation p-values < 0.05 for skeletal muscle and 79 genes associated for the whole blood, such as RCHY1 (PTWAS = 0.001). Those genes were enriched in 112 gene ontology (GO) terms and five Kyoto Encyclopedia of Genes and Genomes pathways, such as ‘chemical carcinogenesis - reactive oxygen species’ (LogP value = −2.139). Further comparing the TWAS significant genes with the differentially expressed genes identified by mRNA expression profiles of LSS found 18 overlapped genes, such as interleukin 15 receptor subunit alpha (IL15RA) (PTWAS = 0.040, PmRNA = 0.010). Moreover, 71 common GO terms were detected for the enrichment results of TWAS and mRNA expression profiles, such as negative regulation of cell differentiation (LogP value = −2.811). Conclusion. This study revealed the genetic mechanism behind the pathological changes in LSS, and may provide novel insights for the early diagnosis and intervention of LSS. Cite this article: Bone Joint Res 2023;12(6):387–396

Aims. Astragalus polysaccharide (APS) participates in various processes, such as the enhancement of immunity and inhibition of tumours. APS can affect osteoporosis (OP) by regulating the osteogenic differentiation of human bone mesenchymal stem cells (hBMSCs). This study was designed to elucidate the mechanism of APS in hBMSC proliferation and osteoblast differentiation. Methods. Reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting were performed to determine the expression of microRNA (miR)-760 and ankyrin repeat and FYVE domain containing 1 (ANKFY1) in OP tissues and hBMSCs. Cell viability was measured using the Cell Counting Kit-8 assay. The expression of cyclin D1 and osteogenic marker genes (osteocalcin (OCN), alkaline phosphatase (ALP), and runt-related transcription factor 2 (RUNX2)) was evaluated using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Mineral deposits were detected through Alizarin Red S staining. In addition, Western blotting was performed to detect the ANKFY1 protein levels following the regulation of miR-760. The relationship between miR-760 and ANKFY1 was determined using a luciferase reporter assay. Results. The expression of miR-760 was upregulated in OP tissues, whereas ANKFY1 expression was downregulated. APS stimulated the differentiation and proliferation of hBMSCs by: increasing their viability; upregulating the expression levels of cyclin D1, ALP, OCN, and RUNX2; and inducing osteoblast mineralization. Moreover, APS downregulated the expression of miR-760. Overexpression of miR-760 was found to inhibit the promotive effect of APS on hBMSC differentiation and proliferation, while knockdown of miR-760 had the opposite effect. ANKFY1 was found to be the direct target of miR-760. Additionally, ANKFY1 participated in the APS-mediated regulation of miR-760 function in hBMSCs. Conclusion. APS promotes the osteogenic differentiation and proliferation of hBMSCs. Moreover, APS alleviates the effects of OP by downregulating miR-760 and upregulating ANKFY1 expression. Cite this article: Bone Joint Res 2023;12(8):476–485

Aims. Deciphering the genetic relationships between major depressive disorder (MDD) and osteoarthritis (OA) may facilitate an understanding of their biological mechanisms, as well as inform more effective treatment regimens. We aim to investigate the mechanisms underlying relationships between MDD and OA in the context of common genetic variations. Methods. Linkage disequilibrium score regression was used to test the genetic correlation between MDD and OA. Polygenic analysis was performed to estimate shared genetic variations between the two diseases. Two-sample bidirectional Mendelian randomization analysis was used to investigate causal relationships between MDD and OA. Genomic loci shared between MDD and OA were identified using cross-trait meta-analysis. Fine-mapping of transcriptome-wide associations was used to prioritize putatively causal genes for the two diseases. Results. MDD has a significant genetic correlation with OA (r. g. = 0.29) and the two diseases share a considerable proportion of causal variants. Mendelian randomization analysis indicates that genetic liability to MDD has a causal effect on OA (b. xy. = 0.24) and genetic liability to OA conferred a causal effect on MDD (b. xy. = 0.20). Cross-trait meta-analyses identified 29 shared genomic loci between MDD and OA. Together with fine-mapping of transcriptome-wide association signals, our results suggest that Estrogen Receptor 1 (ESR1), SRY-Box Transcription Factor 5 (SOX5), and Glutathione Peroxidase 1 (GPX1) may have therapeutic implications for both MDD and OA. Conclusion. The study reveals substantial shared genetic liability between MDD and OA, which may confer risk for one another. Our findings provide a novel insight into phenotypic relationships between MDD and OA. Cite this article: Bone Joint Res 2022;11(1):12–22

Aims. This study aimed to explore the biological and clinical importance of dysregulated key genes in osteoarthritis (OA) patients at the cartilage level to find potential biomarkers and targets for diagnosing and treating OA. Methods. Six sets of gene expression profiles were obtained from the Gene Expression Omnibus database. Differential expression analysis, weighted gene coexpression network analysis (WGCNA), and multiple machine-learning algorithms were used to screen crucial genes in osteoarthritic cartilage, and genome enrichment and functional annotation analyses were used to decipher the related categories of gene function. Single-sample gene set enrichment analysis was performed to analyze immune cell infiltration. Correlation analysis was used to explore the relationship among the hub genes and immune cells, as well as markers related to articular cartilage degradation and bone mineralization. Results. A total of 46 genes were obtained from the intersection of significantly upregulated genes in osteoarthritic cartilage and the key module genes screened by WGCNA. Functional annotation analysis revealed that these genes were closely related to pathological responses associated with OA, such as inflammation and immunity. Four key dysregulated genes (cartilage acidic protein 1 (CRTAC1), iodothyronine deiodinase 2 (DIO2), angiopoietin-related protein 2 (ANGPTL2), and MAGE family member D1 (MAGED1)) were identified after using machine-learning algorithms. These genes had high diagnostic value in both the training cohort and external validation cohort (receiver operating characteristic > 0.8). The upregulated expression of these hub genes in osteoarthritic cartilage signified higher levels of immune infiltration as well as the expression of metalloproteinases and mineralization markers, suggesting harmful biological alterations and indicating that these hub genes play an important role in the pathogenesis of OA. A competing endogenous RNA network was constructed to reveal the underlying post-transcriptional regulatory mechanisms. Conclusion. The current study explores and validates a dysregulated key gene set in osteoarthritic cartilage that is capable of accurately diagnosing OA and characterizing the biological alterations in osteoarthritic cartilage; this may become a promising indicator in clinical decision-making. This study indicates that dysregulated key genes play an important role in the development and progression of OA, and may be potential therapeutic targets. Cite this article: Bone Joint Res 2024;13(2):66–82

Aims. Osteosarcoma is the most common primary bone malignancy among children and adolescents. We investigated whether benzamil, an amiloride analogue and sodium-calcium exchange blocker, may exhibit therapeutic potential for osteosarcoma in vitro. Methods. MG63 and U2OS cells were treated with benzamil for 24 hours. Cell viability was evaluated with the MTS/PMS assay, colony formation assay, and flow cytometry (forward/side scatter). Chromosome condensation, the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay, cleavage of poly-ADP ribose polymerase (PARP) and caspase-7, and FITC annexin V/PI double staining were monitored as indicators of apoptosis. Intracellular calcium was detected by flow cytometry with Fluo-4 AM. The phosphorylation and activation of focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3) were measured by western blot. The expression levels of X-linked inhibitor of apoptosis protein (XIAP), B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), SOD1, and SOD2 were also assessed by western blot. Mitochondrial status was assessed with tetramethylrhodamine, ethyl ester (TMRE), and intracellular adenosine triphosphate (ATP) was measured with BioTracker ATP-Red Live Cell Dye. Total cellular integrin levels were evaluated by western blot, and the expression of cell surface integrins was assessed using fluorescent-labelled antibodies and flow cytometry. Results. Benzamil suppressed growth of osteosarcoma cells by inducing apoptosis. Benzamil reduced the expression of cell surface integrins α5, αV, and β1 in MG63 cells, while it only reduced the expression of αV in U2OS cells. Benzamil suppressed the phosphorylation and activation of FAK and STAT3. In addition, mitochondrial function and ATP production were compromised by benzamil. The levels of anti-apoptotic proteins XIAP, Bcl-2, and Bcl-xL were reduced by benzamil. Correspondingly, benzamil potentiated cisplatin- and methotrexate-induced apoptosis in osteosarcoma cells. Conclusion. Benzamil exerts anti-osteosarcoma activity by inducing apoptosis. In terms of mechanism, benzamil appears to inhibit integrin/FAK/STAT3 signalling, which triggers mitochondrial dysfunction and ATP depletion. Cite this article: Bone Joint Res 2024;13(4):157–168

Aims. The outcomes following nonoperative management of minimally displaced greater tuberosity (GT) fractures, and the factors which influence patient experience, remain poorly defined. We assessed the early patient-derived outcomes following these injuries and examined the effect of a range of demographic- and injury-related variables on these outcomes. Methods. In total, 101 patients (53 female, 48 male) with a mean age of 50.9 years (19 to 76) with minimally displaced GT fractures were recruited to a prospective observational cohort study. During the first year after injury, patients underwent experiential assessment using the Disabilities of the Arm, Shoulder and Hand (DASH) score and assessment of associated injuries using MRI performed within two weeks of injury. The primary outcome was the one-year DASH score. Multivariate analysis was used to assess the effect of patient demographic factors, complications, and associated injuries, on outcome. Results. The mean DASH score improved from 42.3 (SD 9.6) at six weeks post-injury, to 19.5 (SD 14.3) at one-year follow-up (p < 0.001), but outcomes were mixed, with 30 patients having a DASH score > 30 at one year. MRI revealed a range of associated injuries, with a full-thickness rotator cuff tear present in 19 patients (19%). Overall, 11 patients (11%) developed complications requiring further operative intervention; 20 patients (21%) developed post-traumatic secondary shoulder stiffness. Multivariate analysis revealed a high-energy mechanism (p = 0.009), tobacco consumption (p = 0.033), use of mobility aids (p = 0.047), a full-thickness rotator cuff tear (p = 0.002), and the development of post-traumatic secondary shoulder stiffness (p = 0.035) were independent predictors of poorer outcome. Conclusion. The results of nonoperative management of minimally displaced GT fractures are heterogeneous. While many patients have satisfactory early outcomes, a substantial subgroup fare much worse. There is a high prevalence of rotator cuff injuries and post-traumatic shoulder stiffness, and their presence is associated with poorer patient experience. Furthermore, patients who have a high-energy injury, smoke, or use walking aids, have worse outcomes. Cite this article: Bone Joint J 2023;105-B(5):534–542

Aims. The aim of this study was to compare a bicruciate-retaining (BCR) total knee arthroplasty (TKA) with a posterior cruciate-retaining (CR) TKA design in terms of kinematics, measured using fluoroscopy and stability as micromotion using radiostereometric analysis (RSA). Methods. A total of 40 patients with end-stage osteoarthritis were included in this randomized controlled trial. All patients performed a step-up and lunge task in front of a monoplane fluoroscope one year postoperatively. Femorotibial contact point (CP) locations were determined at every flexion angle and compared between the groups. RSA images were taken at baseline, six weeks, three, six, 12, and 24 months postoperatively. Clinical and functional outcomes were compared postoperatively for two years. Results. The BCR-TKA demonstrated a kinematic pattern comparable to the natural knee’s screw-home mechanism in the step-up task. In the lunge task, the medial CP of the BCR-TKA was more anterior in the early flexion phase, while laterally the CP was more posterior during the entire movement cycle. The BCR-TKA group showed higher tibial migration. No differences were found for the clinical and functional outcomes. Conclusion. The BCR-TKA shows a different kinematic pattern in early flexion/late extension compared to the CR-TKA. The difference between both implants is mostly visible in the flexion phase in which the anterior cruciate ligament is effective; however, both designs fail to fully replicate the motion of a natural knee. The higher migration of the BCR-TKA was concerning and highlights the importance of longer follow-up. Cite this article: Bone Joint J 2023;105-B(1):35–46

Aims. Glucose-insulin-potassium (GIK) is protective following cardiac myocyte ischaemia-reperfusion (IR) injury, however the role of GIK in protecting skeletal muscle from IR injury has not been evaluated. Given the similar mechanisms by which cardiac and skeletal muscle sustain an IR injury, we hypothesized that GIK would similarly protect skeletal muscle viability. Methods. A total of 20 C57BL/6 male mice (10 control, 10 GIK) sustained a hindlimb IR injury using a 2.5-hour rubber band tourniquet. Immediately prior to tourniquet placement, a subcutaneous osmotic pump was placed which infused control mice with saline (0.9% sodium chloride) and treated mice with GIK (40% glucose, 50 U/l insulin, 80 mEq/L KCl, pH 4.5) at a rate of 16 µl/hr for 26.5 hours. At 24 hours following tourniquet removal, bilateral (tourniqueted and non-tourniqueted) gastrocnemius muscles were triphenyltetrazolium chloride (TTC)-stained to quantify percentage muscle viability. Bilateral peroneal muscles were used for gene expression analysis, serum creatinine and creatine kinase activity were measured, and a validated murine ethogram was used to quantify pain before euthanasia. Results. GIK treatment resulted in a significant protection of skeletal muscle with increased viability (GIK 22.07% (SD 15.48%)) compared to saline control (control 3.14% (SD 3.29%)) (p = 0.005). Additionally, GIK led to a statistically significant reduction in gene expression markers of cell death (CASP3, p < 0.001) and inflammation (NOS2, p < 0.001; IGF1, p = 0.007; IL-1β, p = 0.002; TNFα, p = 0.012), and a significant reduction in serum creatine kinase (p = 0.004) and creatinine (p < 0.001). GIK led to a significant reduction in IR-related pain (p = 0.030). Conclusion. Systemic GIK infusion during and after limb ischaemia protects murine skeletal muscle from cell death, kidneys from reperfusion metabolites, and reduces pain by reducing post-ischaemic inflammation. Cite this article: Bone Joint Res 2023;12(3):212–218

Aims. Osteoporosis (OP) is a metabolic bone disease, characterized by a decrease in bone mineral density (BMD). However, the research of regulatory variants has been limited for BMD. In this study, we aimed to explore novel regulatory genetic variants associated with BMD. Methods. We conducted an integrative analysis of BMD genome-wide association study (GWAS) and regulatory single nucleotide polymorphism (rSNP) annotation information. Firstly, the discovery GWAS dataset and replication GWAS dataset were integrated with rSNP annotation database to obtain BMD associated SNP regulatory elements and SNP regulatory element-target gene (E-G) pairs, respectively. Then, the common genes were further subjected to HumanNet v2 to explore the biological effects. Results. Through discovery and replication integrative analysis for BMD GWAS and rSNP annotation database, we identified 36 common BMD-associated genes for BMD irrespective of regulatory elements, such as FAM3C (p. discovery GWAS. = 1.21 × 10. -25. , p. replication GWAS. = 1.80 × 10. -12. ), CCDC170 (p. discovery GWAS. = 1.23 × 10. -11. , p. replication GWAS. = 3.22 × 10. -9. ), and SOX6 (p. discovery GWAS. = 4.41 × 10. -15. , p. replication GWAS. = 6.57 × 10. -14. ). Then, for the 36 common target genes, multiple gene ontology (GO) terms were detected for BMD such as positive regulation of cartilage development (p = 9.27 × 10. -3. ) and positive regulation of chondrocyte differentiation (p = 9.27 × 10. -3. ). Conclusion. We explored the potential roles of rSNP in the genetic mechanisms of BMD and identified multiple candidate genes. Our study results support the implication of regulatory genetic variants in the development of OP. Cite this article: Bone Joint Res 2023;12(2):147–154

Aims. The mechanism by which synovial fluid (SF) kills bacteria has not yet been elucidated, and a better understanding is needed. We sought to analyze the antimicrobial properties of exogenous copper in human SF against Staphylococcus aureus. Methods. We performed in vitro growth and viability assays to determine the capability of S. aureus to survive in SF with the addition of 10 µM of copper. We determined the minimum bactericidal concentration of copper (MBC-Cu) and evaluated its sensitivity to killing, comparing wild type (WT) and CopAZB-deficient USA300 strains. Results. UAMS-1 demonstrated a greater sensitivity to SF compared to USA300 WT at 12 hours (p = 0.001) and 24 hours (p = 0.027). UAMS-1 died in statistically significant quantities at 24 hours (p = 0.017), and USA300 WT survived at 24 hours. UAMS-1 was more susceptible to the addition of copper at four (p = 0.001), 12 (p = 0.005), and 24 hours (p = 0.006). We confirmed a high sensitivity to killing with the addition of exogenous copper on both strains at four (p = 0.011), 12 (p = 0.011), and 24 hours (p = 0.011). WT and CopAZB-deficient USA300 strains significantly died in SF, demonstrating a MBC-Cu of 50 µM against USA300 WT (p = 0.011). Conclusion. SF has antimicrobial properties against S. aureus, and UAMS-1 was more sensitive than USA300 WT. Adding 10 µM of copper was highly toxic, confirming its bactericidal effect. We found CopAZB proteins to be involved in copper effluxion by demonstrating the high sensitivity of mutant strains to lower copper concentrations. Thus, we propose CopAZB proteins as potential targets and use exogenous copper as a treatment alternative against S. aureus. Cite this article: Bone Joint Res 2024;13(11):632–646

Aims. Several studies have reported that patients presenting during the evening or weekend have poorer quality healthcare. Our objective was to examine how timely surgery for patients with severe open tibial fracture varies by day and time of presentation and by type of hospital. This cohort study included patients with severe open tibial fractures from the Trauma Audit and Research Network (TARN). Methods. Provision of prompt surgery (debridement within 12 hours and soft-tissue coverage in 72 hours) was examined, using multivariate logistic regression to derive adjusted risk ratios (RRs). Time was categorized into three eight-hour intervals for each day of the week. The models were adjusted for treatment in a major trauma centre (MTC), sex, age, year of presentation, injury severity score, injury mechanism, and number of operations each patient received. Results. We studied 8,258 patients from 175 hospitals. Patients presenting during the day (08:00 to 15:59; risk ratio (RR) 1.11, 95% confidence interval (CI) 1.02 to 1.20) were more likely to receive debridement within 12 hours, and patients presenting at night (16:00 to 23:59; RR 0.56, 95% CI 0.51 to 0.62) were less likely to achieve the target; triage to a MTC had no effect. Day of presentation was associated with soft-tissue coverage within 72 hours; patients presenting on a Thursday or Friday being less likely to receive this surgery within 72 hours (Thursday RR 0.88, 95% CI 0.81 to 0.97; Friday RR 0.89, 95% CI 0.81 to 0.98), and the standard less likely to be achieved for those treated in ‘non-MTC’ hospitals (RR 0.76, 95% CI 0.70 to 0.82). Conclusion. Variations in care were observed for timely surgery for severe open tibial fractures with debridement surgery affected by time of presentation and soft-tissue coverage affected by day of presentation and type of hospital. The variation is unwarranted and highlights that there are opportunities to substantially improve the delivery and quality of care for patients with severe open tibial fracture. Cite this article: Bone Jt Open 2022;3(12):941–952

The anterior cruciate ligament (ACL) is frequently injured in elite athletes, with females up to eight times more likely to suffer an ACL tear than males. Biomechanical and hormonal factors have been thoroughly investigated; however, there remain unknown factors that need investigation. The mechanism of injury differs between males and females, and anatomical differences contribute significantly to the increased risk in females. Hormonal factors, both endogenous and exogenous, play a role in ACL laxity and may modify the risk of injury. However, data are still limited, and research involving oral contraceptives is potentially associated with methodological and ethical problems. Such characteristics can also influence the outcome after ACL reconstruction, with higher failure rates in females linked to a smaller diameter of the graft, especially in athletes aged < 21 years. The addition of a lateral extra-articular tenodesis can improve the outcomes after ACL reconstruction and reduce the risk of failure, and it should be routinely considered in young elite athletes. Sex-specific environmental differences can also contribute to the increased risk of injury, with more limited access to and availablility of advanced training facilities for female athletes. In addition, football kits are designed for male players, and increased attention should be focused on improving the quality of pitches, as female leagues usually play the day after male leagues. The kit, including boots, the length of studs, and the footballs themselves, should be tailored to the needs and body shapes of female athletes. Specific physiotherapy programmes and training protocols have yielded remarkable results in reducing the risk of injury, and these should be extended to school-age athletes. Finally, psychological factors should not be overlooked, with females’ greater fear of re-injury and lack of confidence in their knee compromising their return to sport after ACL injury. Both intrinsic and extrinsic factors should be recognized and addressed to optimize the training programmes which are designed to prevent injury, and improve our understanding of these injuries. Cite this article: Bone Joint J 2023;105-B(10):1033–1037

Aims. Spinopelvic characteristics influence the hip’s biomechanical behaviour. However, to date there is little knowledge defining what ‘normal’ spinopelvic characteristics are. This study aims to determine how static spinopelvic characteristics change with age and ethnicity among asymptomatic, healthy individuals. Methods. This systematic review followed the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines to identify English studies, including ≥ 18-year-old participants, without evidence of hip or spine pathology or a history of previous surgery or interventional treatment, documenting lumbar lordosis (LL), sacral slope (SS), pelvic tilt (PT), and pelvic incidence (PI). From a total of 2,543 articles retrieved after the initial database search, 61 articles were eventually selected for data extraction. Results. When all ethnicities were combined the mean values for LL, SS, PT, and PI were: 47.4° (SD 11.0°), 35.8° (SD 7.8°), 14.0° (SD 7.2°), and 48.8° (SD 10°), respectively. LL, SS, and PT had statistically significant (p < 0.001) changes per decade at: −1.5° (SD 0.3°), −1.3° (SD 0.3°), and 1.4° (SD 0.1°). Asian populations had the largest age-dependent change in LL, SS, and PT compared to any other ethnicity per decade at: −1.3° (SD 0.3°) to −0.5° (SD 1.3°), –1.2° (SD 0.2°) to −0.3° (SD 0.3°), and 1.7° (SD 0.2°) versus 1.1° (SD 0.1°), respectively. Conclusion. Ageing alters the orientation between the spine and pelvis, causing LL, SS, and PT to modify their orientations in a compensatory mechanism to maintain sagittal alignment for balance when standing. Asian populations have the largest degree of age-dependent change to their spinopelvic parameters compared to any other ethnicity, likely due to their lower PI. Cite this article: Bone Joint Res 2023;12(4):231–244

Aims. CRP is an acute-phase protein that is used as a biomarker to follow severity and progression in infectious and inflammatory diseases. Its pathophysiological mechanisms of action are still poorly defined. CRP in its pentameric form exhibits weak anti-inflammatory activity. The monomeric isoform (mCRP) exerts potent proinflammatory properties in chondrocytes, endothelial cells, and leucocytes. No data exist regarding mCRP effects in human intervertebral disc (IVD) cells. This work aimed to verify the pathophysiological relevance of mCRP in the aetiology and/or progression of IVD degeneration. Methods. We investigated the effects of mCRP and the signalling pathways that are involved in cultured human primary annulus fibrosus (AF) cells and in the human nucleus pulposus (NP) immortalized cell line HNPSV-1. We determined messenger RNA (mRNA) and protein levels of relevant factors involved in inflammatory responses, by quantitative real-time polymerase chain reaction (RT-qPCR) and western blot. We also studied the presence of mCRP in human AF and NP tissues by immunohistochemistry. Results. We demonstrated that mCRP increases nitric oxide synthase 2 (NOS2), cyclooxygenase 2 (COX2), matrix metalloproteinase 13 (MMP13), vascular cell adhesion molecule 1 (VCAM1), interleukin (IL)-6, IL-8, and Lipocalin 2 (LCN2) expression in human AF and NP cells. We also showed that nuclear factor-κβ (NF-κβ), extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphoinositide 3-kinase (PI3K) are at play in the intracellular signalling of mCRP. Finally, we demonstrated the presence of mCRP in human AF and NP tissues. Conclusion. Our results indicate, for the first time, that mCRP can be localized in IVD tissues, where it triggers a proinflammatory and catabolic state in degenerative and healthy IVD cells, and that NF-κβ signalling may be implicated in the mediation of this mCRP-induced state. Cite this article: Bone Joint Res 2023;12(3):189–198

Aims. The aim of this study was to determine the fracture haematoma (fxH) proteome after multiple trauma using label-free proteomics, comparing two different fracture treatment strategies. Methods. A porcine multiple trauma model was used in which two fracture treatment strategies were compared: early total care (ETC) and damage control orthopaedics (DCO). fxH was harvested and analyzed using liquid chromatography-tandem mass spectrometry. Per group, discriminating proteins were identified and protein interaction analyses were performed to further elucidate key biomolecular pathways in the early fracture healing phase. Results. The early fxH proteome was characterized by immunomodulatory and osteogenic proteins, and proteins involved in the coagulation cascade. Treatment-specific proteome alterations were observed. The fxH proteome of the ETC group showed increased expression of pro-inflammatory proteins related to, among others, activation of the complement system, neutrophil functioning, and macrophage activation, while showing decreased expression of proteins related to osteogenesis and tissue remodelling. Conversely, the fxH proteome of the DCO group contained various upregulated or exclusively detected proteins related to tissue regeneration and remodelling, and proteins related to anti-inflammatory and osteogenic processes. Conclusion. The early fxH proteome of the ETC group was characterized by the expression of immunomodulatory, mainly pro-inflammatory, proteins, whereas the early fxH proteome of the DCO group was more regenerative and osteogenic in nature. These findings match clinical observations, in which enhanced surgical trauma after multiple trauma causes dysbalanced inflammation, potentially leading to reduced tissue regeneration, and gained insights into regulatory mechanisms of fracture healing after severe trauma. Cite this article: Bone Joint Res 2024;13(5):214–225

Aims. To explore the synovial expression of mucin 1 (MUC1) and its role in rheumatoid arthritis (RA), as well as the possible downstream mechanisms. Methods. Patients with qualified synovium samples were recruited from a RA cohort. Synovium from patients diagnosed as non-inflammatory orthopaedic arthropathies was obtained as control. The expression and localization of MUC1 in synovium and fibroblast-like synoviocytes were assessed by immunohistochemistry and immunofluorescence. Small interfering RNA and MUC1 inhibitor GO-203 were adopted for inhibition of MUC1. Lysophosphatidic acid (LPA) was used as an activator of Rho-associated pathway. Expression of inflammatory cytokines, cell migration, and invasion were evaluated using quantitative real-time polymerase chain reaction (PCR) and Transwell chamber assay. Results. A total of 63 RA patients and ten controls were included. Expression of MUC1 was observed in both the synovial lining and sublining layer. The percentage of MUC1+ cells in the lining layer of synovium was significantly higher in RA than that in control, and positively correlated to joint destruction scores of RA. Meanwhile, MUC1+ cells in the sublining layer were positively correlated to the Krenn subscore of inflammatory infiltration. Knockdown of MUC1, rather than GO-203 treatment, ameliorated the expression of proinflammatory cytokines, cell migration, and invasion of rheumatoid synoviocytes. Knockdown of MUC1 decreased expression of RhoA, Cdc42, and Rac1. Treatment with LPA compromised the inhibition of migration and invasion, but not inflammation, of synoviocytes by MUC1 knockdown. Conclusion. Upregulated MUC1 promotes the aggression of rheumatoid synoviocytes via Rho guanosine triphosphatases (GTPases), thereby facilitating synovitis and joint destruction during the pathological process of RA. Cite this article: Bone Joint Res 2022;11(9):639–651

Aims. The aim of this study was to compare the biomechanical models of two frequently used techniques for reconstructing severe acetabular defects with pelvic discontinuity in revision total hip arthroplasty (THA) – the Trabecular Metal Acetabular Revision System (TMARS) and custom triflange acetabular components (CTACs) – using virtual modelling. Methods. Pre- and postoperative CT scans from ten patients who underwent revision with the TMARS for a Paprosky IIIB acetabular defect with pelvic discontinuity were retrospectively collated. Computer models of a CTAC implant were designed from the preoperative CT scans of these patients. Computer models of the TMARS reconstruction were segmented from postoperative CT scans using a semi-automated method. The amount of bone removed, the implant-bone apposition that was achieved, and the restoration of the centre of rotation of the hip were compared between all the actual TMARS and the virtual CTAC implants. Results. The median amount of bone removed for TMARS reconstructions was significantly greater than for CTAC implants (9.07 cm. 3. (interquartile range (IQR) 5.86 to 21.42) vs 1.16 cm. 3. (IQR 0.42 to 3.53) (p = 0.004). There was no significant difference between the median overall implant-bone apposition between TMARS reconstructions and CTAC implants (54.8 cm. 2. (IQR 28.2 to 82.3) vs 56.6 cm. 2. (IQR 40.6 to 69.7) (p = 0.683). However, there was significantly more implant-bone apposition within the residual acetabulum (45.2 cm. 2. (IQR 28.2 to 72.4) vs 25.5 cm. 2. (IQR 12.8 to 44.1) (p = 0.001) and conversely significantly less apposition with the outer cortex of the pelvis for TMARS implants compared with CTAC reconstructions (0 cm. 2. (IQR 0 to 13.1) vs 23.2 cm. 2. (IQR 16.4 to 30.6) (p = 0.009). The mean centre of rotation of the hip of TMARS reconstructions differed by a mean of 11.1 mm (3 to 28) compared with CTAC implants. Conclusion. In using TMARS, more bone is removed, thus achieving more implant-bone apposition within the residual acetabular bone. In CTAC implants, the amount of bone removed is minimal, while the implant-bone apposition is more evenly distributed between the residual acetabulum and the outer cortex of the pelvis. The differences suggest that these implants used to treat pelvic discontinuity might achieve short- and long-term stability through different biomechanical mechanisms. Cite this article: Bone Joint J 2024;106-B(5 Supple B):74–81