Aims. To examine how eukaryotic translation initiation factor 5A (eIF5A) regulates osteoarthritis (OA) during mechanical overload and the specific mechanism. Methods. Histological experiments used human bone samples and C57BL/6J mice knee samples. All cell experiments were performed using mice primary chondrocytes. Messenger RNA (mRNA) sequencing was performed on chondrocytes treated with 20% cyclic tensile strain for 24 hours. Western blot (WB) and quantitative polymerase chain reaction were employed to detect relevant indicators of cartilage function in chondrocytes. We created the destabilization of the medial meniscus (DMM) model and the mechanical overload-induced OA model and injected with overexpressing eIF5A adenovirus (eIF5A-ADV). Cartilage degeneration was evaluated using Safranin O/Fast Green staining. Relative protein levels were ascertained by immunohistochemistry (IHC) and immunofluorescence (IF) staining. Results. After OA initiation, eIF5A caused an upregulation of type II collagen (COL2) and a downregulation of matrix metalloproteinase 13 (MMP13), P16, and P21, which postponed the aggravation of OA. Further sequencing and experimental findings revealed that eIF5A knockdown accelerated the progression of OA by boosting the expression of histone acetyltransferase cyclic-adenosine monophosphate response element binding protein (CREB)-binding protein (CREBBP) to mediate activation of the Notch pathway. Conclusion. Our findings identified a crucial functional mechanism for the onset of OA, and suggest that intra-articular eIF5A injections might be a useful therapeutic strategy for OA treatment. Cite this article: Bone Joint Res 2025;14(2):124–135

Osteoarthritis (OA) is a highly prevalent and disabling disease with an unmet therapeutic need. The characteristic cartilage loss and alteration of other joint structures result from a complex interaction of multiple risk factors, with mechanical overload consistently playing a central role. This overload generates an inflammatory response in the cartilage due to the activation of the innate immune response in chondrocytes, which occurs through various cellular mechanisms. Moreover, risk factors associated with obesity, being overweight, and metabolic syndrome enhance the inflammatory response both locally and systemically. OA chondrocytes, the only cells present in articular cartilage, are therefore inflamed and initiate an anabolic process in an attempt to repair the damaged tissue, which ultimately results in an aberrant and dysfunctional process. Under these circumstances, where the cartilage continues to be subjected to chronic mechanical stress, proposing a treatment that stimulates the chondrocytes’ anabolic response to restore tissue structure does not appear to be a therapeutic target with a high likelihood of success. In fact, anabolic drugs proposed for the treatment of OA have yet to demonstrate efficacy. By contrast, multiple therapeutic strategies focused on pharmacologically managing the inflammatory component, both at the joint and systemic levels, have shown promise. Therefore, prioritizing the control of chronic innate pro-inflammatory pathways presents the most viable and promising therapeutic strategy for the effective management of OA. As research continues, this approach may offer the best opportunity to alleviate the burden of this incapacitating disease. Cite this article: Bone Joint Res 2025;14(3):199–207

Aims. Excessive chondrocyte hypertrophy is a common feature in cartilage degeneration which is susceptible to joint overloading, but the relationship between mechanical overloading and chondrocyte hypertrophy still remains elusive. The aim of our study was to explore the mechanism of mechanical compression-induced chondrocyte hypertrophy. Methods. In this study, the temporomandibular joint (TMJ) degeneration model was built through forced mandibular retrusion (FMR)-induced compression in TMJ. Chondrocytes were also mechanically compressed in vitro. The role of O-GlcNAcylation in mechanical compression-induced chondrocyte hypertrophy manifested through specific activator Thiamet G and inhibitor OSMI-1. Results. Both in vivo and in vitro data revealed that chondrocyte hypertrophic differentiation is promoted by compression. Immunofluorescent and immunoblotting results showed that protein pan-O-GlcNAcylation levels were elevated in these hypertrophic chondrocytes. Pharmacologically inhibiting protein pan-O-GlcNAcylation by OSMI-1 partially mitigated the compression-induced hypertrophic differentiation of chondrocytes. Specifically, runt-related transcription factor 2 (Runx2) and SRY-Box 9 transcription factor (Sox9) were subjected to modification of O-GlcNAcylation under mechanical compression, and pharmacological activation or inhibition of O-GlcNAcylation affected the transcriptional activity of Runx2 but not Sox9. Furthermore, compression-induced protein pan-O-GlcNAcylation in chondrocytes was induced by enhanced expression of glucose transporter 1 (GLUT1), and depletion of GLUT1 by WZB117 dampened the effect of compression on chondrocyte hypertrophy. Conclusion. Our study proposes a novel function of GLUT1-mediated protein O-GlcNAcylation in driving compression-induced hypertrophic differentiation of chondrocytes by O-GlcNAc modification of Runx2, which promoted its transcriptional activity and strengthened the expressions of downstream hypertrophic marker. Cite this article: Bone Joint Res 2025;14(3):209–222

As high incidences of tendinopathies are observed particularly in those who intensively use their tendons, we assume that pathological changes are caused, at least partially, by mechanical overload. This has led to the so-called overload hypothesis, explaining the development of tendinopathies by structural failure resulting from excessive load. At the same time, tendon loading is an important part in tendon rehabilitation. Currently, exercise treatment approaches such as eccentric training or heavy load resistance training are widely applied in tendinopathy rehabilitation, with good clinical results such as an improvement in function and a reduction in pain. Particularly those rehabilitative approaches which impose high strains on the tendon may induce an adaptation of the tendon's mechanical properties such as increased tendon stiffness. An increased tendon stiffness is often interpreted as desirable, as it may protect the tendon from overloading and thus prevent future strain injuries. However, the tendinopathic tendon is not necessarily less stiff than the tendon in the contralateral leg and an improvement in tendon stiffness is not necessarily accompanied by an improvement in tendon pain or function. In addition, metabolic factors, resulting e.g. in low-level systemic inflammation, may contribute to pathological tendon tissue changes and are not necessarily affected by an exercise program, while nutritional interventions or dietary supplements may potentially affect tendon cell metabolism. Indeed, dietary supplements have been introduced as an additional therapeutic approach in the treatment of tendinopathies in recent years, and their positive curative effects have been reported for both the general population and athletes. In the management of tendinopathies, it may thus be advisable if therapeutic approaches aim to address both tendon mechanics and tendon metabolism for better treatment effectiveness and a sustainable improvement in pain and function

Tendinopathy is the most frequent musculoskeletal disease that requires medical attention. Mechanical overload has been considered as a key driver of its pathology. However, the underline mechanism on how overload induces tendinopathy and inflammation is unclear. Extracellular mitochondria (EM) are newly identified as cell-to-cell communicators. The aim of this study is to elucidate the role of mitochondria in overload-induced inflammation. We performed three-dimensional uniaxial stretching to mouse tendon organoid in bioreactors. Cyclic strain of uniaxial loadings included underload, normal load, and overload, according to previous work. We then harvested microvesicles including EM, from the bioreactor by differential centrifugation and evaluated their characteristics by flow cytometry and super-resolution confocal microscopy. Raw 264.7 mouse macrophage cell line was used for chemotaxis assay in a Boyden Chamber System with Magnetic-Activated Cell Sorting Technology. EM induced cytokines secretion by macrophages was analyzed by a bead-based multiplex assay panel. N-Acetyl-L-cysteine (NAC) was used as the antioxidant to tendon organoid to regulate mitochondrial fitness. We showed mechanical load induced tendon organoid to release microvesicles including mitochondria. The size of microvesicles is mainly in the range from 220nm to 880nm. More than 75% of microvesicles could be stained by PKH26, confirming they were with lipophilic membrane. Super-resolution confocal microscopy identified two forms of mitochondria, including mitochondria encapsulated in vesicles and free mitochondria. Overload led to the degeneration of the organoid and induced microvesicles release containing most EM. Chemotaxis assay showed that EM from overloaded tendon organoid induced macrophages chemotaxis. In addition, microvesicles extracted from overloaded tendon organoid induced the production of proinflammatory cytokines including IL-6, KC (Keratinocyte-Derived Chemokine) and IL-18. NAC treatment to tendon cells could attenuate overload-induced macrophage chemotaxis. Overload induces EM releasing from tendon cells, which leads to chemotaxis of macrophages toward tendon, resulting in induction of inflammation

Tendinopathy is one of the most common orthopaedic pathological conditions characterized by tendon degenerative changes. Excessive mechanical loading is considered as a major causative factor in the development of tendinopathy, but the mechanisms of pathogenesis remain unclear. High mobility group box-1 (HMGB1), a potent inflammatory mediator when released into the matrix, has been identified in the early stage tendinopathy patients. Since the release and contribution of HMGB1 in tendinopathy development due to mechanical overloading is unknown, we investigated the role of HMGB1 in tendinopathy using a mouse intensive treadmill running (ITR) model and injection of glycyrrhizin (GL), a specific inhibitor of HMGB1. A total of 48 mice were divided into four groups, Cage Control group: The animals were allowed to move freely in their cage, GL group: The animals were received daily IP injection of GL (50 mg/kg body weight) for 24 weeks, ITR group: The animals ran on treadmill at 15 meters/min for three h/ day, five days a week for 12 or 24 weeks, GL+ITR group: The animals ran the same protocol as that of ITR group plus daily IP injection of GL for 12 or 24 weeks. Six mice/group were sacrificed at 12 or 24 weeks and the Achilles and patellar tendon tissues were harvested and used for histochemical staining and immunostaining. Mechanical overloading induced HMGB1 released from the cell nuclei to the matrix (Fig. 1a, b) caused tendon inflammation (Fig. 1c, d) and led to tendon degenerative changes (Fig. 1e-j). After 12 weeks of ITR, the tendon tissue near the bone insertion site showed typical tendinopathic changes in cell shape, accumulation of glycosaminoglycans (GAG) (Fig. 1e, f), and increase in SOX-9 staining (Fig. 1g-j). After 24 weeks ITR, the distal site of Achilles tendon showed considerable changes in cell shape (Fig. 2A, g, arrows), which is round compared to more elongated in the control and GL groups (Fig. 2A, e, f). However, daily treatment with GL prior to ITR blocked the cell shape change (Fig. 2A, h) and, ITR induced extensive GAG accumulation in ITR group (Fig. 2B, bottom panel). Furthermore, GL inhibited ITR-induced expression of chondrogenic markers (SOX-9 and collagen II) in the tendons (Fig. 3). Our results showed that mechanical overloading-induced HMGB1 plays a critical role in the development of tendinopathy by initiating tendon inflammation and eventual degeneration characterized by the presence of chondrocyte-like cells, accumulation of proteoglycans, high levels of collagen type II production, and chondrogenic marker SOX-9 expression. These results provide the first evidence for the role of HMGB1 as a therapeutic target to prevent tendinopathy before its onset and block further development at its early inflammation stages. The inhibition of tendinopathy development by GL administration in this study also suggests the putative therapeutic potential of this natural triterpene that is already in clinical use to treat other inflammation-related diseases. For any figures or tables, please contact authors directly

Abstract. OBJECTIVE. Knee varus malalignment increases medial knee compartment loading and is associated with knee osteoarthritis (OA) progression and severity. 1. Altered biomechanical loading and dysregulation of joint tissue biology drive OA progression, but mechanistic links between these factors are lacking. Subchondral bone structural changes are biomechanically driven, involve bone resorption, immune cell influx, angiogenesis, and sensory nerve invasion, and contribute to joint destruction and pain. 2. We have investigated mechanisms underlying this involving RANKL and alkaline phosphatase (ALP), which reflect bone resorption and mineralisation respectively. 3. and the axonal guidance factor Sema3A. Sema3A is osteotropic, expressed by mechanically sensitive osteocytes, and an inhibitor of sensory nerve, blood vessel and immune cell invasion. 4. Sema3A is also differentially expressed in human OA bone. 5. HYPOTHESIS: Medial knee compartment overloading in varus knee malalignment patients causes dysregulation of bone derived Sema3A signalling directly linking joint biomechanics to pathology and pain. METHODS. Synovial fluid obtained from 30 subjects with medial knee OA (KL grade II-IV) undergoing high tibial osteotomy surgery (HTO) was analysed by mesoscale discovery and ELISA analysis for inflammatory, neural and bone turnover markers. 11 of these patients had been previously analysed in a published patient-specific musculoskeletal model. 6. of gait estimating joint contact location, pressure, forces, and medial-lateral condyle load distribution in a published data set included in analyses. Data analysis was performed using Pearson's correlation matrices and principal component analyses. Principal Components (PCs) with eigenvalues greater than 1 were analysed. RESULTS. PC1 (32.94% of variation) and PC2 (25.79% of variation) from PCA analysis and correlation matrices separated patients according to correlated clusters of established inflammatory markers of OA pain and progression (IL6/IL8, r=0.754, p<0.001) and anti-inflammatory mediators (IL4/IL10, r=0.469, p=0.005). Bone turnover marker ALP was positively associated with KL grade (r=0.815, p=0.002) and negatively associated with IL10 (r=−0.402, p=0.018) and first peak knee loading pressures (r=−0.688, p=0.019). RANKL was positively associated with IL4 (r=0.489, p=0.003). Synovial fluid Sema3A concentrations showed separate clustering from all OA progression markers and was inversely correlated with TNF-α (r=−0.423, p=0.022) in HTO patients. Sema3A was significantly inversely correlated with total predicted force in the medial joint compartment (r=−0.621, p=0.041), mean (r=−0.63, p=0.038) and maximum (r=−0.613, p=0.045) calculated medial compartment joint pressures during the first phase and mean (r=−0.618, p=0.043) and maximum (r=−0.641, p=0.034) medial compartment joint pressures during midstance outputs of patient-specific musculoskeletal model. CONCLUSIONS. This study shows joint inflammatory status and mechanical overloading influence subchondral bone-remodelling. Synovial Sema3A concentrations are inversely correlated to patient-specific musculoskeletal model estimations of pathological medial overloading. This study reveals Sema3A as a biological mediator with capacity to induce OA pain and disease progression that is directly regulated by gait mechanical loading. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Varus malalignment increases the susceptibility of cartilage to mechanical overloading, which stimulates catabolic metabolism to break down the extracellular matrix and lead to osteoarthritis (OA). The altered mechanical axis from the hip, knee to ankle leads to knee joint pain and ensuing cartilage wear and deterioration, which impact millions of the aged population. Stabilization of the remaining damaged cartilage, and prevention of further deterioration, could provide immense clinical utility and prolong joint function. Our previous work showed that high tibial osteotomy (HTO) could shift the mechanical stress from an imbalanced status to a neutral alignment. However, the underlying mechanisms of endogenous cartilage stabilization after HTO remain unclear. We hypothesize that cartilage-resident mesenchymal stem cells (MSCs) dampen damaged cartilage injury and promote endogenous repair in a varus malaligned knee. The goal of this study is to further examine whether HTO-mediated off-loading would affect human cartilage-resident MSCs' anabolic and catabolic metabolism. This study was approved by IACUC at Xi'an Jiaotong University. Patients with medial compartment OA (52.75±6.85 yrs, left knee 18, right knee 20) underwent open-wedge HTO by the same surgeons at one single academic sports medicine center. Clinical data was documented by the Epic HIS between the dates of April 2019 and April 2022 and radiographic images were collected with a minimum of 12 months of follow-up. Medial compartment OA with/without medial meniscus injury patients with unilateral Kellgren /Lawrence grade 3–4 was confirmed by X-ray. All incisions of the lower extremity healed well after the HTO operation without incision infection. Joint space width (JSW) was measured by uploading to ImageJ software. The Knee injury and Osteoarthritis Outcome Score (KOOS) toolkit was applied to assess the pain level. Outerbridge scores were obtained from a second-look arthroscopic examination. RNA was extracted to quantify catabolic targets and pro-inflammatory genes (QiaGen). Student's t test for two group comparisons and ANOVA analysis for differences between more than 2 groups were utilized. To understand the role of mechanical loading-induced cartilage repair, we measured the serial changes of joint space width (JSW) after HTO for assessing the state of the cartilage stabilization. Our data showed that HTO increased the JSW, decreased the VAS score and improved the KOOS score significantly. We further scored cartilage lesion severity using the Outerbridge classification under a second-look arthroscopic examination while removing the HTO plate. It showed the cartilage lesion area decreased significantly, the full thickness of cartilage increased and mechanical strength was better compared to the pre-HTO baseline. HTO dampened medial tibiofemoral cartilage degeneration and accelerate cartilage repair from Outerbridge grade 2 to 3 to Outerbridge 0 to 1 compared to untreated varus OA. It suggested that physical loading was involved in HTO-induced cartilage regeneration. Given that HTO surgery increases joint space width and creates a physical loading environment, we hypothesize that HTO could increase cartilage composition and collagen accumulation. Consistent with our observation, a group of cartilage-resident MSCs was identified. Our data further showed decreased expression of RUNX2, COL10 and increased SOX9 in MSCs at the RNA level, indicating that catabolic activities were halted during mechanical off-loading. To understand the role of cartilage-resident MSCs in cartilage repair in a biophysical environment, we investigated the differentiation potential of MSCs under 3-dimensional mechanical loading conditions. The physical loading inhibited catabolic markers (IL-1 and IL-6) and increased anabolic markers (SOX9, COL2). Knee-preserved HTO intervention alleviates varus malalignment-related knee joint pain, improves daily and recreation function, and repairs degenerated cartilage of medial compartment OA. The off-loading effect of HTO may allow the mechanoregulation of cartilage repair through the differentiation of endogenous cartilage-derived MSCs

Introduction and Objective. Chronic tendinopathy is a multifactorial disease and a common problem in both, athletes and the general population. Mechanical overload and in addition old age, adiposity, and metabolic disorders are among the risk factors for chronic tendinopathy but their role in the pathogenesis is not yet unequivocally clarified. Materials and Methods. Achilles tendons of young (10 weeks) and old (100 weeks) female rats bred for high (HCR) and low (LCR) intrinsic aerobic exercise capacity were investigated. Both Achilles tendons of 28 rats were included and groups were young HCR, young LCR, old HCR, and old LCR (n = 7 tendons per group/method). In this rat model, genetically determined aerobic exercise capacity is associated with a certain phenotype as LCR show higher body weight and metabolic dysfunctions in comparison to HCR. Quantitative real-time PCR (qPCR) was used to evaluate alterations in gene expression. For histological analysis, semi-automated image analysis and histological scoring were performed. Results. Age-related downregulation of tenocyte marker genes (Tenomodulin), genes related to matrix modelling and remodeling (Collagen type 1, Collagen type 3, Elastin, Biglycan, Fibronectin, Tenascin C), and Transforming growth factor beta 3 (Tgfb3) were detected in tendons from HCR and LCR. Furthermore, inflammatory marker Cyclooxygenase 2 (Cox2) was downregulated, while Microsomal prostaglandin E synthase 2 (Ptges2) was upregulated in tendons from old HCR and old LCR. No significant alteration was seen in Interleukin 6 (Il6), Interleukin 1 beta (Il1b), and Tumor necrosis factor alpha (Tnfa). Histological analysis revealed that Achilles tendons of old rats had fewer and more elongated tenocyte nuclei compared to young rats, indicating a reduced metabolic activity. Even though higher content of glycosaminoglycans as a sign of degeneration was found in tendons of old HCR and LCR, no further signs of tendinopathy were detectable in histological evaluation. Conclusions. Overall, aging seems to play a prominent role in molecular and structural alterations of Achilles tendon tissue, while low intrinsic exercise capacity did not cause any changes. Even though tendinopathy was not present in any of the groups, some of the shown age-related changes correspond to single characteristics of chronic tendon disease. This study gives an insight into tendon aging and its contribution to molecular and cellular changes in Achilles tendon tissue

Intervertebral disc degeneration (IDD) is a major cause of low back pain, which affects 80% of the adult population at least once in their life. The pathophysiological conditions underlying IDD are still poorly understood. Genetic makeup, aging, smoking, physical inactivity and mechanical overloading, especially due to obesity, are among the strongest risk factors involved. Moreover, IDD is often associated with chronic inflammation within disc tissues, which increases matrix breakdown, glycosaminoglycan (GAG) loss and cell death. This micro-inflammatory environment is typical of several metabolic disorders, including diabetes mellitus (DM). As the etiopathogenesis of IDD in diabetic subjects remains scarcely understood, we hypothesised that this may be driven by a DM-induced inflammation leading to a combination of reduced GAG levels, decreased proteoglycan synthesis and increased matrix breakdown within the disc. The objective of the study was to investigate the pathogenesis of IDD in a murine model of type 1 DM (T1DM), namely non-obese diabetic (NOD) mouse. Total disc glycosaminoglycan (GAG) content, proteoglycan synthesis, aggrecan fragmentation mediated by matrix metalloproteinases (MMPs) and a Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS), glucose transporter (mGLUT1) gene expression and apoptosis (TUNEL assay) were assessed in NOD mice and wild-type euglycemic control mice. Spinal structural and molecular changes were analysed by micro-computed tomography (mCT), histological staining (Safranin-O and fast green) and quantitative immunofluorescence (anti-ADAMTS-4 and 5 antibodies). Statistical analysis was conducted considering the average of 35 samples ± standard error for each measurement, with 95% confidence intervals calculated to determine statistical significance (p-value < 0.05). IVDs of NOD mice showed increased disc apoptosis (p < 0.05) and higher aggrecan fragmentation mediated by ADAMTS (p < 0.05). However, ADAMTS-4 and −5 did not appear to be involved in this process. The total GAG content normalized to DNA and PG synthesis showed no statistically significant alterations, as well as Safranin O staining. Although not significantly, NOD mice showed reduced glucose uptake. In addition, the vertebral structure of NOD mice at mCT seemed not to be altered. These data demonstrate that DM may contribute to IDD by increasing aggrecan degradation and promoting cell apoptosis, which may represent early indicators of the involvement of DM in the pathogenesis of IDD

Osteoarthritis (OA) is the most common joint disease, which is characterized by a progressive loss of proteoglycans and the destruction of extracellular matrix (ECM), leading to a loss of cartilage integrity and joint function. During OA development, chondrocytes alter ECM synthesis and change their gene expression profile including upregulation of hypertrophic markers known from the growth plate. Although physiological mechanical loading can support cartilage formation and maintenance, mechanical overload represents one major risk factor for OA development. To date, little is known on how an OA-like hypertrophic chondrocyte phenotype alters the response of cartilage tissue to mechanical loading. The aim of this study was to investigate whether a hypertrophic phenotype change of chondrocytes affects the response to physiological mechanical loading and to reveal differences compared to normal control cartilage. Cartilage replacement tissue was generated using human articular chondrocytes (normal control cartilage, n=3–5) or human mesenchymal stromal cells which develop a hypertrophic phenotype similar to the one observed in OA (OA cartilage model, n=3–6). Cells were seeded in a collagen type I/III carrier and attached to a beta-TCP bone replacement phase, building an osteochondral unit for simulation of natural conditions. After 21 and 35 days of chondrogenic (re)differentiation, a single physiological mechanical compression episode (1 Hz, 25 %, 3 h) was applied, imitating three hours of normal walking in ten-minute intervals. Proteoglycan and collagen synthesis, gene expression and activation of signaling pathways were assessed. Cartilage replacement tissue of both groups had similar proteoglycan and collagen type II content as well as hardness properties. During (re)differentiation, both cell types showed a comparable upregulation of the chondrogenic marker genes COL2A1 and ACAN. As expected, hypertrophic marker genes (COL10A1, ALPL, MEF2C, IBSP) were only upregulated in the OA cartilage model. Mechanotransduction in both tissues was confirmed by load-induced activation of pERK1/2 signaling. While the 3 h loading episode significantly increased proteoglycan synthesis in normal control cartilage at day 35, the same protocol resulted in a suppression of proteoglycan and collagen synthesis in the OA cartilage model, which was accompanied by a downregulation of COL2A1 gene expression. In addition, hypertrophic marker genes COL10A1, ALPL and IBSP were significantly reduced after loading. Along lower load-induced SOX9 mRNA and protein stimulation in the OA cartilage tissue, a weaker induction of mechanosensitive BMP2, BMP6, FOS and FOSB gene expression was observed. While stable cartilage showed anabolic effects after physiological loading, the hypertrophic chondrocytes reacted with a reduced extracellular matrix synthesis. This could be explained by a lower mechanoinduction of the BMP signaling cascade and insufficient SOX9 stimulation. Progressive OA development could thus be influenced by a reduced mechanocompetence of osteoarthritic chondrocytes

Purpose of study and background. Mechanical overloading initiates intervertebral disc degeneration, presumably because cells break down the extracellular matrix (ECM). We used Fourier Transform Infrared Spectroscopy (FTIR) imaging to identify, visualize and quantify the ECM and aimed to identify spectroscopic markers for early disc degeneration. Methods and Results. In seven goats, one disc was injected with chondroitinase ABC (mild degeneration) and after three months compared to control. Ex vivo, 50 caprine discs received physiological loading (50–150N) or overloading (50–400N) in a loaded disc culture system. To determine whether ECM degeneration is due to cell activity, half of the discs was subjected to freeze-thaw cycles. Spectroscopic images were collected at 1000–1300 cm. −1. and analyzed using multivariate curve resolution analysis. In vivo, less proteoglycan was found in the degenerated group (p<0.05), especially in the nucleus. Collagen content was increased in the nucleus and anterior annulus, and had higher entropy (p<0.01), indicating matrix disorganization. In the ex vivo experiment, the proteoglycan/collagen ratio was decreased (p<0.05) in the vital group and there was an increase in collagen entropy (p<0.05). A significant interaction between loading and vitality was found in the amount of collagen (p<0.05), but not in the entropy. Conclusion. Three weeks of mild overloading causes measurable changes in the extracellular matrix. Increased collagen entropy indicates that remodeling of collagen is a first step into disc degeneration. We could not confirm, however, that increase in entropy was due to cell activity. FTIR imaging allows more detailed investigation of early disc degeneration than traditional measures. There are no conflicts of interest. Partially funded by Dutch Arthritis Funds, personal grant KSE

INTRODUCTION. Mechanical overloading of the knee can occur during activities of daily living such as stair climbing, jogging, etc. In this finite element study we aim to investigate which parameters could detrimentally influence peri-implant bone in the tibial reconstructed knee. Bone quality and patient variables are potential factors influencing knee overloading (Zimmerman 2016). METHODS. Finite element (FE) models of post-mortem retrieved tibial specimens (n=7) from a previous study (Zimmerman 2016) were created using image segmentation (Mimics Materialise v14) of CT scan data (0.6 mm voxel resolution). Tibial tray and polyethylene inserts were recreated from CT data and measurements of the specimens (Solidworks 2015). Specimens with varying implant geometry (keel/pegged) were chosen for this study. A cohesive layer between bone and cement was included to simulate the behavior of the bone–cement interface using experimentally obtained values. The FE models predict plasticity of bone according to Keyak (2005). Models were loaded to 10 body weight (BW) and then reduced to 1 BW to mimic experimental measurements. Axial FE bone strains at 1 BW were compared with experimental Digital Image Correlation (DIC) bone strains on cut sections of the specimens. After validation of the FE models using strain data, models were rotated and translated to the coordinate system defined in Bergmann (2014). Four loading cases were chosen – walking, descending stairs, sitting down and jogging. Element strains were written to file for post-processing. The bone in all FE models was divided into regions of equal thickness (10 mm) for comparison of strains. RESULTS. Results are shown for two specimens at present. Strain-maps of the specimen cut section compare reasonably well with FE cutting-plane strains. The FE models however show some regions of high strain in certain locations which do not correspond with the experimental results (Figure 1). Plasticity predicted by the models at 10 BW is shown in Figure 2. Median bone strains for two loading cases are shown as a function of distance below the tibial tray in Figure 3. This figure shows that specimen 1 is less likely to be overloaded during jogging when compared with specimen 2. Both specimens remain below the 7300 με threshold for compressive yield. DISCUSSION. Using functioning knee replacement tibial specimens, we study which factors influence bone overloading. Validation using DIC strain measurements is challenging due to the large plasticity regions predicted by the material model used here. The present results were obtained using plasticity relationships from Keyak (2005) for the proximal femur. To further improve on our results, plasticity-bone density relationships for the proximal tibia (Keyak 1996) will be included. Proximal tibial bone has been shown to be stiffer than femoral bone (Morgan 2003). Despite these limitations, FE models provide valuable information on the risk of overloading during daily living activities. The study will be expanded to include an analysis of implant geometry, bone quality and other loading cases. For any figures or tables, please contact the authors directly

Femoroacetabular impingement (FAI) causes pain and chondrolabral damage via mechanical overload during movement of the hip. It is caused by many different types of pathoanatomy, including the cam ‘bump’, decreased head–neck offset, acetabular retroversion, global acetabular overcoverage, prominent anterior–inferior iliac spine, slipped capital femoral epiphysis, and the sequelae of childhood Perthes’ disease. Both evolutionary and developmental factors may cause FAI. Prevalence studies show that anatomic variations that cause FAI are common in the asymptomatic population. Young athletes may be predisposed to FAI because of the stress on the physis during development. Other factors, including the soft tissues, may also influence symptoms and chondrolabral damage. FAI and the resultant chondrolabral pathology are often treated arthroscopically. Although the results are favourable, morphologies can be complex, patient expectations are high and the surgery is challenging. The long-term outcomes of hip arthroscopy are still forthcoming and it is unknown if treatment of FAI will prevent arthrosis

The cause of elbow tendinosis is most likely a combination of mechanical overloading and abnormal microvascular responses. Numerous methods of treatment have been advocated. In this study, we evaluated the use of platelet-rich plasma (PRP) as a treatment for resistant epicondylitis. The rationale for using platelets is that they participate predominantly in the early inflammation phases and degranulation. They constitute a reservoir of critical growth factors and cytokines which when placed directly into the damaged tissue, may govern and regulate the tissue healing process. We looked at 25 patients (19 with lateral and 6 with medial) who failed to improve after physiotherapy, cortisone injections and application of epicondylar clasps and assessed the efficacy of platelet-rich plasma injections using Gravitational platelet separation system (GPS). The cohort of patients included over a period of three years had physiotherapy, stretches, epicondylar clasp and an average of 2.9steroid injections (1–6) before having a PRP injection. The mean patient age was 43 years ranging between 24 and 54. There were 11 men and 14 women. The study included 19 patients with lateral epicondylitis and 6 patients with symptoms on the medial side. The ratio between dominant and nondominant side was according to the literature: 76%. The quick DASH scores imroved by 14% on an average in the first 3 months and further 26% in the following 9 months. 4 patients needed reintervention, 3 lateral and 1 medial and had surgical release between 6 and 12 months. 2 of them had reinjections before surgery. No local infections except mild inflammation and no systemic effects were noted. Within the limitations of being a case series and limited follow-up PRP injections provided a safe and progressive benefit over a period of 1 year in refractory cases, providing a good nonoperative alternative

Summary Statement. An organ culture experiment was simulated to explore the mechanisms that can link cell death to mechanical overload in the intervertebral disc. Coupling cell nutrition and tissue deformations led to altered metabolic transport that largely explained cell viability measurements. Introduction. Part of intervertebral disc (IVD) maintenance relies on limited nutrient availability to the cells and on mechanical loads, but effective implication of these two factors is difficult to quantify. Theoretical models have helped to understand the link between solute transport and cell nutrition in deforming IVD, but omitted the direct link between tissue mechanics and cell metabolism. Hence, we explored numerically the relation between disc mechanics and cell death in relation to an organ culture experiment. Methods. A finite element model of a caudal bovine IVD was created to reproduce an organ culture experiment. All subtissues were modelled, and coupled to cell metabolism in two ways: (i) mechanical strains and metabolic reactions were simply coupled to the diffusions of oxygen, lactate and glucose through a mechano-transport algorithm (IND model). (ii), a hypermetabolism model based on in vitro data involved a 30% increase in glucose consumption by the cells, activated either as a Step or as a Gaussian function over 15% strain (DIR model). Exponential decays of cell density occurred below 0.5 mM of glucose and/or below pH 6.78. Concentrations of 21 kPa oxygen and 4.5 mM glucose were imposed at the boundary, and a combination of 0.2 MPa compression and 10° bending was applied over 7 days. Results. The highest hypermetabolic response was given by the Step activation. For all models, cell death mostly occurred in the compressed area of the flexed IVD, and steady-state cell viability was reached in about two days of load. In the outer annulus fibrosus (AF), the DIR model with Step activation led to increased cell death, in line with the cell viability measured in vitro. In the inner AF, all cell viability results matched the reported measurements. Discussion/Conclusion. This study focused on elucidating the links between mechanical stimulation and cell survival in the IVD, and simulation of nutrition issues allowed reproducing the results of an organ culture experiment. Results suggest that mechano-regulated metabolism can play a significant role in the nutrition-related cell death. Truly, the IND model gave both low glucose and low pH, and altered metabolic transport represented the main cell death mechanism. Yet, the role of hypermetabolism was increased nearby the nutrient supply at the outer AF, meaning that cell death could occur, even in regions where nutrient supply seems ensured by short diffusion distances. Though further mechanistic developments must be considered, this novel mechano-regulated metabolism model permits mechano-transport models to be used to explore important interactions between tissue biophysics and multiphysics. In particular, the extracellular matrix degradation along degeneration and cell death can be coupled to the poromechanical parameters introduced, e.g. initial porosity and osmotic pressure values that largely depend on the proteoglycan concentration

Aims

In this study, we aimed to evaluate incidence trends and potential risk factors associated with Perthes’ disease in Denmark, using publicly available data.

Introduction: Unicompartmental knee arthroplasty (UKA) is a proven for treatment of knee osteoarthritis (OA). Survival rates have been found comparable with total knee arthroplasty (TKA) in specialty hospitals series, but registry based studies show worse results of survival of UKA. High BMI, age of the patient, patellofemoral arthritis or learning curve have been found to have only mild consequences to the survival rates. Original indications for Oxford UKA in OA are severe pain and full thickness cartilage loss with bone-on-bone contact in the medial side. After widespread use of UKA surgeons are broadening their indications. Purpose of this study was to evaluate the influence of preoperative degree of OA on survival rate of UKA. Material and Methods: 113 knees in 103 patients were operated with Oxford phase 3 UKA. We evaluated all the patient data retrospectively and patient age, body mass index (BMI), sex, earlier arthroscopies, operation time, follow-up time, preoperative medial joint space widths, reoperations and survival of UKA was recorded. Results: The mean age of the patients was 58 years (38–81) and mean follow-up time was 47 months (3–114). 22 UKAs were revised and the overall survival rate was 80.5%. 68% of revised knees have had undergone arthroscopy before UKA to confirm existence of arthritis. Odds ratio for female gender was statistically non-significant 1.59 (95% CI 0.57–4.45, p=0.46,). For BMI and patient’s age, the association remained non-significant with odds ratios of 1.07 (95% CI 0.98–1.17, p=0.14) and 0.96 (95% CI 0.90–1.02, p=0.19). Patients were divided four sub-groups according medial joint space width (medial joint space width ≤2 mm and > 2 mm) and Lateral/medial joint space width ratio (L/M-ratio ≤2.5 and > 2.5). Over 2 mm medial joint space width or L/M-ratio less than 2.5 were found significant risk factors for revisions, odds ratios being 6.00 (95% CI 2.12–17.00, p< 0.01) and 7.88 (95% CI 2.76–22.54, p< 0.01), respectively. Discussion: Nowadays UKAs are performed on patients with mild OA against the original indications. In more severe OA varus alignment of the knee causes mechanical overload to the medial compartment, which is well corrected by UKA. Also it is possible that in the cases of prolonged knee pain caution is focused incorrectly to mild OA, which is typical radiological finding even in asymptomatic middle aged and elderly patients. Also in the early phase of OA it is impossible to estimate progression of cartilage damage in other two compartments. In conclusion we suggest that not to extend original indication of UKA and patient should have true medial bone-on-bone OA in preoperative radiographs. Performing UKA for patients with medial joint space width over 2 mm or L/M-ratio less than 2.5 should be concerned particularly careful

Aims

The Exeter V40 cemented polished tapered stem system has demonstrated excellent long-term outcomes. This paper presents a systematic review of the existing literature and reports on a large case series comparing implant fractures between the Exeter V40 series; 125 mm and conventional length stem systems.

Objectives

The role of mechanical stress and transforming growth factor beta 1 (TGF-β1) is important in the initiation and progression of osteoarthritis (OA). However, the underlying molecular mechanisms are not clearly known.