Objectives. Whilst gait speed is variable between healthy and injured adults, the extent to which speed alone alters the 3D in vivo knee kinematics has not been fully described. The purpose of this prospective study was to understand better the spatiotemporal and 3D knee kinematic changes induced by slow compared with normal self-selected walking speeds within young healthy adults. Methods. A total of 26 men and 25 women (18 to 35 years old) participated in this study. Participants walked on a treadmill with the KneeKG system at a slow imposed speed (2 km/hr) for three trials, then at a self-selected comfortable walking speed for another three trials. Paired t-tests, Wilcoxon signed-rank tests, Mann-Whitney U tests and Spearman’s rank correlation coefficients were conducted using Stata/IC 14 to compare kinematics of slow versus self-selected walking speed. Results. Both cadence and step length were reduced during slow gait compared with normal gait. Slow walking reduced flexion during standing (10.6° compared with 13.7°; p < 0.0001), and flexion range of movement (ROM) (53.1° compared with 57.3°; p < 0.0001). Slow walking also induced less adduction ROM (8.3° compared with 10.0°; p < 0.0001), rotation ROM (11.4. °. compared with 13.6. °. ; p < 0.0001), and anteroposterior translation ROM (8.5 mm compared with 10.1 mm; p < 0.0001). Conclusion. The reduced spatiotemporal measures, reduced flexion during stance, and knee ROM in all planes induced by slow walking demonstrate a stiff knee gait, similar to that previously demonstrated in osteoarthritis. Further research is required to determine if these characteristics induced in healthy knees by slow walking provide a valid model of osteoarthritic gait. Cite this article: N. Mannering, T. Young, T. Spelman, P. F. Choong. Three-dimensional knee kinematic analysis during treadmill gait: Slow imposed speed versus normal self-selected speed. Bone Joint Res 2017;6:514–521. DOI: 10.1302/2046-3758.68.BJR-2016-0296.R1

Objectives. To elucidate the effects of age on the expression levels of the receptor activator of the nuclear factor-κB ligand (RANKL) and osteoclasts in the periodontal ligament during orthodontic mechanical loading and post-orthodontic retention. Materials and Methods. The study included 20 male Sprague-Dawley rats, ten in the young group (aged four to five weeks) and ten in the adult group (aged 18 to 20 weeks). In each rat, the upper-left first molar was subjected to a seven-day orthodontic force loading followed by a seven-day retention period. The upper-right first molar served as a control. The amount of orthodontic tooth movement was measured after seven-day force application and seven-day post-orthodontic retention. The expression levels of RANKL and the tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts were evaluated on day 7 (end of mechanical force loading) and day 14 (after seven days of post-orthodontic retention). Statistical analysis was performed using the t-test, and significance was set at p < 0.05. Results. There was no significant difference between the amount of tooth movement in the young group (0.96, standard deviation (. sd. ) 0.30mm) and that in the adult group (0.80mm, . sd. 0.28) (p > 0.05) after the seven-day force application. On the compression side, the expression of RANKL and TRAP-positive osteoclasts in both the young and the adult groups increased after the application of force for seven days, and then decreased at the end of the seven-day retention period. However, by the end of the period, the expression of RANKL on the compression side dropped to the control level in the young group (p > 0.05), while it was still higher than that on the control side in the adult group (p < 0.05). The expression of RANKL on the compression side did not show significant difference between the young and the adult groups after seven-day force application (p > 0.05), but it was significantly higher in the adult group than that in the young group after seven-day post-orthodontic retention (p < 0.05). Similarly, the decreasing trend of TRAP-positive osteoclasts during the retention period in the adult group was less obvious than that in the young group. Conclusions. The bone-resorptive activity in the young rats was more dynamic than that in the adult rats. The expression of RANKL and the number of osteoclasts in adult rats did not drop to the control level during the post-orthodontic retention period while RANKL expression and the number of osteoclasts in young rats had returned to the baseline. Cite this article: X. Li, M. Li, J. Lu, Y. Hu, L. Cui, D. Zhang, Y. Yang. Age-related effects on osteoclastic activities after orthodontic tooth movement. Bone Joint Res 2016;5:492–499. DOI: 10.1302/2046-3758.510.BJR-2016-0004.R2

Objectives. Cellular movement and relocalisation are important for many physiologic properties. Local mesenchymal stem cells (MSCs) from injured tissues and circulating MSCs aid in fracture healing. Cytokines and chemokines such as Stromal cell-derived factor 1(SDF-1) and its receptor chemokine receptor type 4 (CXCR4) play important roles in maintaining mobilisation, trafficking and homing of stem cells from bone marrow to the site of injury. We investigated the differences in migration of MSCs from the femurs of young, adult and ovariectomised (OVX) rats and the effect of CXCR4 over-expression on their migration. Methods. MSCs from young, adult and OVX rats were put in a Boyden chamber to establish their migration towards SDF-1. This was compared with MSCs transfected with CXCR4, as well as MSCs differentiated to osteoblasts. Results. MSCs from OVX rats migrate significantly (p < 0.05) less towards SDF-1 (9%, . sd. 5%) compared with MSCs from adult (15%, . sd. 3%) and young rats (25%, . sd. 4%). Cells transfected with CXCR4 migrated significantly more towards SDF-1 compared with non-transfected cells, irrespective of whether these cells were from OVX (26.5%, . sd. 4%), young (47%, . sd. 17%) or adult (21%, . sd. 4%) rats. Transfected MSCs differentiated to osteoblasts express CXCR4 but do not migrate towards SDF-1. Conclusions. MSC migration is impaired by age and osteoporosis in rats, and this may be associated with a significant reduction in bone formation in osteoporotic patients. The migration of stem cells can be ameliorated by upregulating CXCR4 levels which could possibly enhance fracture healing in osteoporotic patients. Cite this article: A. Sanghani-Kerai, M. Coathup, S. Samazideh, P. Kalia, L. Di Silvio, B. Idowu, G. Blunn. Osteoporosis and ageing affects the migration of stem cells and this is ameliorated by transfection with CXCR4. Bone Joint Res 2017;6:–365. DOI: 10.1302/2046-3758.66.BJR-2016-0259.R1

Objectives. Platelet-rich plasma (PRP) is being used increasingly often in the clinical setting to treat tendon-related pathologies. Yet the optimal PRP preparations to promote tendon healing in different patient populations are poorly defined. Here, we sought to determine whether increasing the concentration of platelet-derived proteins within a derivative of PRP, platelet lysate (PL), enhances tenocyte proliferation and migration in vitro, and whether the mitogenic properties of PL change with donor age. Methods. Concentrated PLs from both young (< 50 years) and aged (> 50 years) donors were prepared by exposing pooled PRP to a series of freeze-thaw cycles followed by dilution in plasma, and the levels of several platelet-derived proteins were measured using multiplex immunoassay technology. Human tenocytes were cultured with PLs to simulate a clinically relevant PRP treatment range, and cell growth and migration were assessed using DNA quantitation and gap closure assays, respectively. Results. Platelet-derived protein levels increased alongside higher PL concentrations, and PLs from both age groups improved tenocyte proliferation relative to control conditions. However, PLs from aged donors yielded a dose-response relationship in tenocyte behaviour, with higher PL concentrations resulting in increased tenocyte proliferation and migration. Conversely, no significant differences in tenocyte behaviour were detected when increasing the concentration of PLs from younger donors. Conclusion. Higher PL concentrations, when prepared from the PRP of aged but not young donors, were more effective than lower PL concentrations at promoting tenocyte proliferation and migration in vitro. Cite this article: D. R. Berger, C. J. Centeno, N. J. Steinmetz. Platelet lysates from aged donors promote human tenocyte proliferation and migration in a concentration-dependent manner. Bone Joint Res 2019;8:32–40. DOI: 10.1302/2046-3758.81.BJR-2018-0164.R1

Objectives. The present study describes a novel technique for revitalising allogenic intrasynovial tendons by combining cell-based therapy and mechanical stimulation in an ex vivo canine model. Methods. Specifically, canine flexor digitorum profundus tendons were used for this study and were divided into the following groups: (1) untreated, unprocessed normal tendon; (2) decellularised tendon; (3) bone marrow stromal cell (BMSC)-seeded tendon; and (4) BMSC-seeded and cyclically stretched tendon. Lateral slits were introduced on the tendon to facilitate cell seeding. Tendons from all four study groups were distracted by a servohydraulic testing machine. Tensile force and displacement data were continuously recorded at a sample rate of 20 Hz until 200 Newton of force was reached. Before testing, the cross-sectional dimensions of each tendon were measured with a digital caliper. Young’s modulus was calculated from the slope of the linear region of the stress-strain curve. The BMSCs were labeled for histological and cell viability evaluation on the decellularized tendon scaffold under a confocal microscope. Gene expression levels of selected extracellular matrix tendon growth factor genes were measured. Results were reported as mean ± SD and data was analyzed with one-way ANOVAs followed by Tukey’s post hoc multiple-comparison test. Results. We observed no significant difference in cross-sectional area or in Young’s modulus among the four study groups. In addition, histological sections showed that the BMSCs were aligned well and viable on the tendon slices after two-week culture in groups three and four. Expression levels of several extracellular matrix tendon growth factors, including collagen type I, collagen type III, and matrix metalloproteinase were significantly higher in group four than in group three (p < 0.05). Conclusion. Lateral slits introduced into de-cellularised tendon is a promising method of delivery of BMSCs without compromising cell viability and tendon mechanical properties. In addition, mechanical stimulation of a cell-seeded tendon can promote cell proliferation and enhance expression of collagen types I and III in vitro. Cite this article: J. H. Wu, A. R. Thoreson, A. Gingery, K. N. An, S. L. Moran, P. C. Amadio, C. Zhao. The revitalisation of flexor tendon allografts with bone marrow stromal cells and mechanical stimulation: An ex vivo model revitalising flexor tendon allografts. Bone Joint Res 2017;6:179–185. DOI: 10.1302/2046-3758.63.BJR-2016-0207.R1

Objectives. Meniscal injuries are often associated with an active lifestyle. The damage of meniscal tissue puts young patients at higher risk of undergoing meniscal surgery and, therefore, at higher risk of osteoarthritis. In this study, we undertook proof-of-concept research to develop a cellularized human meniscus by using 3D bioprinting technology. Methods. A 3D model of bioengineered medial meniscus tissue was created, based on MRI scans of a human volunteer. The Digital Imaging and Communications in Medicine (DICOM) data from these MRI scans were processed using dedicated software, in order to obtain an STL model of the structure. The chosen 3D Discovery printing tool was a microvalve-based inkjet printhead. Primary mesenchymal stem cells (MSCs) were isolated from bone marrow and embedded in a collagen-based bio-ink before printing. LIVE/DEAD assay was performed on realized cell-laden constructs carrying MSCs in order to evaluate cell distribution and viability. Results. This study involved the realization of a human cell-laden collagen meniscus using 3D bioprinting. The meniscus prototype showed the biological potential of this technology to provide an anatomically shaped, patient-specific construct with viable cells on a biocompatible material. Conclusion. This paper reports the preliminary findings of the production of a custom-made, cell-laden, collagen-based human meniscus. The prototype described could act as the starting point for future developments of this collagen-based, tissue-engineered structure, which could aid the optimization of implants designed to replace damaged menisci. Cite this article: G. Filardo, M. Petretta, C. Cavallo, L. Roseti, S. Durante, U. Albisinni, B. Grigolo. Patient-specific meniscus prototype based on 3D bioprinting of human cell-laden scaffold. Bone Joint Res 2019;8:101–106. DOI: 10.1302/2046-3758.82.BJR-2018-0134.R1

Objectives. This study aimed to evaluate the histological and mechanical features of tendon healing in a rabbit model with second-harmonic-generation (SHG) imaging and tensile testing. Materials and Methods. A total of eight male Japanese white rabbits were used for this study. The flexor digitorum tendons in their right leg were sharply transected, and then were repaired by intratendinous stitching. At four weeks post-operatively, the rabbits were killed and the flexor digitorum tendons in both right and left legs were excised and used as specimens for tendon healing (n = 8) and control (n = 8), respectively. Each specimen was examined by SHG imaging, followed by tensile testing, and the results of the two testing modalities were assessed for correlation. Results. While the SHG light intensity of the healing tendon samples was significantly lower than that of the uninjured tendon samples, 2D Fourier transform SHG images showed a clear difference in collagen fibre structure between the uninjured and the healing samples, and among the healing samples. The mean intensity of the SHG image showed a moderate correlation (R. 2. = 0.37) with Young’s modulus obtained from the tensile testing. Conclusion. Our results indicate that SHG microscopy may be a potential indicator of tendon healing. Cite this article: E. Hase, K. Sato, D. Yonekura, T. Minamikawa, M. Takahashi, T. Yasui. Evaluation of the histological and mechanical features of tendon healing in a rabbit model with the use of second-harmonic-generation imaging and tensile testing. Bone Joint Res 2016;5:577–585. DOI: 10.1302/2046-3758.511.BJR-2016-0162.R1

Objectives. The objectives of this study were: 1) to examine osteophyte formation, subchondral bone advance, and bone marrow lesions (BMLs) in osteoarthritis (OA)-prone Hartley guinea pigs; and 2) to assess the disease-modifying activity of an orally administered phosphocitrate ‘analogue’, Carolinas Molecule-01 (CM-01). Methods. Young Hartley guinea pigs were divided into two groups. The first group (n = 12) had drinking water and the second group (n = 9) had drinking water containing CM-01. Three guinea pigs in each group were euthanized at age six, 12, and 18 months, respectively. Three guinea pigs in the first group were euthanized aged three months as baseline control. Radiological, histological, and immunochemical examinations were performed to assess cartilage degeneration, osteophyte formation, subchondral bone advance, BMLs, and the levels of matrix metalloproteinse-13 (MMP13) protein expression in the knee joints of hind limbs. Results. In addition to cartilage degeneration, osteophytes, subchondral bone advance, and BMLs increased with age. Subchondral bone advance was observed as early as six months, whereas BMLs and osteophytes were both observed mainly at 12 and 18 months. Fibrotic BMLs were found mostly underneath the degenerated cartilage on the medial side. In contrast, necrotic BMLs were found almost exclusively in the interspinous region. Orally administered CM-01 decreased all of these pathological changes and reduced the levels of MMP13 expression. Conclusion. Subchondral bone may play a role in cartilage degeneration. Subchondral bone changes are early events; formation of osteophytes and BMLs are later events in the OA disease process. Carolinas Molecule-01 is a promising small molecule candidate to be tested as an oral disease-modifying drug for human OA therapy. Cite this article: Y. Sun, A. J. Kiraly, A. R. Sun, M. Cox, D. R. Mauerhan, E. N. Hanley Jr. Effects of a phosphocitrate analogue on osteophyte, subchondral bone advance, and bone marrow lesions in Hartley guinea pigs. Bone Joint Res 2018;7:157–165. DOI:10.1302/2046-3758.72.BJR-2017-0253

Aims

Metaphyseal tritanium cones can be used to manage the tibial bone loss commonly encountered at revision total knee arthroplasty (rTKA). Tibial stems provide additional fixation and are generally used in combination with cones. The aim of this study was to examine the role of the stems in the overall stability of tibial implants when metaphyseal cones are used for rTKA.

Aims

Second-generation metal-on-metal (MoM) articulations in total hip arthroplasty (THA) were introduced in order to reduce wear-related complications. The current study reports on the serum cobalt levels and the clinical outcome at a minimum of 20 years following THA with a MoM (Metasul) or a ceramic-on-polyethylene (CoP) bearing.

Objectives. An experimental piglet model induces avascular necrosis (AVN) and deformation of the femoral head but its secondary effects on the developing acetabulum have not been studied. The aim of this study was to assess the development of secondary acetabular deformation following femoral head ischemia. Methods. Intracapsular circumferential ligation at the base of the femoral neck and sectioning of the ligamentum teres were performed in three week old piglets. MRI was then used for qualitative and quantitative studies of the acetabula in operated and non-operated hips in eight piglets from 48 hours to eight weeks post-surgery. Specimen photographs and histological sections of the acetabula were done at the end of the study. . Results. The operated-side acetabula were wider, shallower and misshapen, with flattened labral edges. At eight weeks, increased acetabular cartilage thickness characterised the operated sides compared with non-operated sides (p < 0.001, ANOVA). The mean acetabular width on the operated side was increased (p = 0.015) while acetabular depth was decreased anteriorly (p = 0.007) and posteriorly (p = 0.44). The cartilage was thicker, with delayed acetabular bone formation, and showed increased vascularisation with fibrosis laterally and focal degenerative changes involving chondrocyte hypocellularity, chondrocyte cloning, peripheral pannus formation and surface fibrillation. . Conclusions. We demonstrate that femoral head AVN in the young growing piglet also induced, and was coupled with, secondary malformation in acetabular shape affecting both articular and adjacent pelvic cartilage structure, and acetabular bone. The femoral head model inducing AVN can also be applied to studies of acetabular maldevelopment, which is less well understood in terms of developing hip malformation. Cite this article: Bone Joint Res 2014;3:130–8

Objectives

Adult mice lacking the transcription factor NFAT1 exhibit osteoarthritis (OA). The precise molecular mechanism for NFAT1 deficiency-induced osteoarthritic cartilage degradation remains to be clarified. This study aimed to investigate if NFAT1 protects articular cartilage (AC) against OA by directly regulating the transcription of specific catabolic and anabolic genes in articular chondrocytes.

Objectives

In this study, we compared the pain behaviour and osteoarthritis (OA) progression between anterior cruciate ligament transection (ACLT) and osteochondral injury in surgically-induced OA rat models.

Objectives

This study aimed to examine the effects of SRT1720, a potent SIRT1 activator, on osteoarthritis (OA) progression using an experimental OA model.

Objectives

The aim of this study was to systematically review the literature on measurement of muscle strength in patients with femoroacetabular impingement (FAI) and other pathologies and to suggest guidelines to standardise protocols for future research in the field.

Objectives

We have previously investigated an association between the genome copy number variation (CNV) and acetabular dysplasia (AD). Hip osteoarthritis is associated with a genetic polymorphism in the aspartic acid repeat in the N-terminal region of the asporin (ASPN) gene; therefore, the present study aimed to investigate whether the CNV of ASPN is involved in the pathogenesis of AD.

Objectives

The aim of the current study was to assess whether calcaneal broadband ultrasound attenuation (BUA) can predict whole body and regional dual-energy x-ray absorptiometry (DXA)-derived bone mass in healthy, Australian children and adolescents at different stages of maturity.

Objectives

Ubiquitin E3 ligase-mediated protein degradation regulates osteoblast function. Itch, an E3 ligase, affects numerous cell functions by regulating ubiquitination and proteasomal degradation of related proteins. However, the Itch-related cellular and molecular mechanisms by which osteoblast differentiation and function are elevated during bone fracture repair are as yet unknown.

Intermittently administered parathyroid hormone (PTH 1-34) has been shown to promote bone formation in both human and animal studies. The hormone and its analogues stimulate both bone formation and resorption, and as such at low doses are now in clinical use for the treatment of severe osteoporosis. By varying the duration of exposure, parathyroid hormone can modulate genes leading to increased bone formation within a so-called ‘anabolic window’. The osteogenic mechanisms involved are multiple, affecting the stimulation of osteoprogenitor cells, osteoblasts, osteocytes and the stem cell niche, and ultimately leading to increased osteoblast activation, reduced osteoblast apoptosis, upregulation of Wnt/β-catenin signalling, increased stem cell mobilisation, and mediation of the RANKL/OPG pathway. Ongoing investigation into their effect on bone formation through ‘coupled’ and ‘uncoupled’ mechanisms further underlines the impact of intermittent PTH on both cortical and cancellous bone. Given the principally catabolic actions of continuous PTH, this article reviews the skeletal actions of intermittent PTH 1-34 and the mechanisms underlying its effect.

Cite this article: L. Osagie-Clouard, A. Sanghani, M. Coathup, T. Briggs, M. Bostrom, G. Blunn. Parathyroid hormone 1-34 and skeletal anabolic action: The use of parathyroid hormone in bone formation. Bone Joint Res 2017;6:14–21. DOI: 10.1302/2046-3758.61.BJR-2016-0085.R1.