The role of the anterior shoulder joint capsule in primary glenohumeral osteoarthritis.

The pathogenesis of primary glenohumeral arthritis (GHOA) is mediated by a complex interaction between osseous anatomy and the surrounding soft tissues. Recently, there has been growing interest in characterizing the association between the anterior shoulder joint capsule and primary GHOA because of the potential for targeted treatment interventions. Emerging evidence has shown substantial synovitis, fibrosis, and mixed inflammatory cell infiltrate in the anterior capsule of osteoarthritic shoulders. In addition, increased thickening of the anterior shoulder joint capsule has been associated with greater posterior glenoid wear and humeral head subluxation. While these findings suggest that anterior capsular disease may play a causative role in the etiology and progression of eccentric GHOA, further studies are needed to support this association. The purpose of this article is to review the pathogenesis of primary GHOA, contextualize current hypotheses regarding the role of the anterior capsule in the disease process, and provide directions for future research.

Preclinical tendon and ligament models: Beyond the 3Rs (replacement, reduction, and refinement) to 5W1H (why, who, what, where, when, how).

Several tendon and ligament animal models were presented at the 2022 Orthopaedic Research Society Tendon Section Conference held at the University of Pennsylvania, May 5 to 7, 2022. A key objective of the breakout sessions at this meeting was to develop guidelines for the field, including for preclinical tendon and ligament animal models. This review summarizes the perspectives of experts for eight surgical small and large animal models of rotator cuff tear, flexor tendon transection, anterior cruciate ligament tear, and Achilles tendon injury using the framework: "Why, Who, What, Where, When, and How" (5W1H). A notable conclusion is that the perfect tendon model does not exist; there is no single gold standard animal model that represents the totality of tendon and ligament disease. Each model has advantages and disadvantages and should be carefully considered in light of the specific research question. There are also circumstances when an animal model is not the best approach. The wide variety of tendon and ligament pathologies necessitates choices between small and large animal models, different anatomic sites, and a range of factors associated with each model during the planning phase. Attendees agreed on some guiding principles including: providing clear justification for the model selected, providing animal model details at publication, encouraging sharing of protocols and expertise, improving training of research personnel, and considering greater collaboration with veterinarians. A clear path for translating from animal models to clinical practice was also considered as a critical next step for accelerating progress in the tendon and ligament field.

Tendon-derived matrix crosslinking techniques for electrospun multi-layered scaffolds.

Tendon tears are common and healing often occurs incompletely and by fibrosis. Tissue engineering seeks to improve repair, and one approach under investigation uses cell-seeded scaffolds containing biomimetic factors. Retention of biomimetic factors on the scaffolds is likely critical to maximize their benefit, while minimizing the risk of adverse effects, and without losing the beneficial effects of the biomimetic factors. The aim of the current study was to evaluate cross-linking methods to enhance the retention of tendon-derived matrix (TDM) on electrospun poly(ε-caprolactone) (PCL) scaffolds. We tested the effects of ultraviolet (UV) or carbodiimide (EDC:NHS:COOH) crosslinking methods to better retain TDM to the scaffolds and stimulate tendon-like matrix synthesis. Initially, we tested various crosslinking configurations of carbodiimide (2.5:1:1, 5:2:1, and 10:4:1 EDC:NHS:COOH ratios) and UV (30 s 1 J/cm2 , 60 s 1 J/cm2 , and 60 s 4 J/cm2 ) on PCL films compared to un-crosslinked TDM. We found that no crosslinking tested retained more TDM than coating alone (Kruskal-Wallis: p > .05), but that human adipose stem cells (hASCs) spread most on the 60 s 1 J/cm2 UV- and 2.5:1:1 EDC-crosslinked films (Kruskal-Wallis: p < .05). Next, we compared the effects of 60 s 1 J/cm2 UV- and 2.5:1:1 EDC-crosslinked to TDM-coated and untreated PCL scaffolds on hASC-induced tendon-like differentiation. UV-crosslinked scaffolds had greater modulus and stiffness than PCL or TDM scaffolds, and hASCs spread more on UV-crosslinked scaffolds (ANOVA: p < .05). Fourier transform infrared spectra revealed that UV- or EDC-crosslinking TDM did not affect the peaks at wavenumbers characteristic of tendon. Crosslinking TDM to electrospun scaffolds improves tendon-like matrix synthesis, providing a viable strategy for improving retention of TDM on electrospun PCL scaffolds.

Aging and obesity prime the methylome and transcriptome of adipose stem cells for disease and dysfunction.

The epigenome of stem cells occupies a critical interface between genes and environment, serving to regulate expression through modification by intrinsic and extrinsic factors. We hypothesized that aging and obesity, which represent major risk factors for a variety of diseases, synergistically modify the epigenome of adult adipose stem cells (ASCs). Using integrated RNA- and targeted bisulfite-sequencing in murine ASCs from lean and obese mice at 5- and 12-months of age, we identified global DNA hypomethylation with either aging or obesity, and a synergistic effect of aging combined with obesity. The transcriptome of ASCs in lean mice was relatively stable to the effects of age, but this was not true in obese mice. Functional pathway analyses identified a subset of genes with critical roles in progenitors and in diseases of obesity and aging. Specifically, Mapt, Nr3c2, App, and Ctnnb1 emerged as potential hypomethylated upstream regulators in both aging and obesity (AL vs. YL and AO vs. YO), and App, Ctnnb1, Hipk2, Id2, and Tp53 exhibited additional effects of aging in obese animals. Furthermore, Foxo3 and Ccnd1 were potential hypermethylated upstream regulators of healthy aging (AL vs. YL), and of the effects of obesity in young animals (YO vs. YL), suggesting that these factors could play a role in accelerated aging with obesity. Finally, we identified candidate driver genes that appeared recurrently in all analyses and comparisons undertaken. Further mechanistic studies are needed to validate the roles of these genes capable of priming ASCs for dysfunction in aging- and obesity-associated pathologies.

Research perspectives-Pipelines to human tendon transcriptomics.

Tendon transcriptomics is a rapidly growing field in musculoskeletal biology. The ultimate aim of many current tendon transcriptomic studies is characterization of in vitro, ex vivo, or in vivo, healthy, and diseased tendon microenvironments to identify the underlying pathways driving human tendon pathology. The transcriptome interfaces between genomic, proteomic, and metabolomic signatures of the tendon cellular niche and the response of this niche to stimuli. Some of the greatest bottlenecks in tendon transcriptomics relate to the availability and quality of human tendon tissue, hence animal tissues are frequently used even though human tissue is most translationally relevant. Here, we review the variability associated with human donor and procurement factors, such as whether the tendon is cadaveric or a clinical remnant, and how these variables affect the quality and relevance of the transcriptomes obtained. Moreover, age, sex, and health demographic variables impact the human tendon transcriptome. Tendons present tissue-specific challenges for cell, nuclei, and RNA extraction that include a dense extracellular matrix, low cellularity, and therefore low RNA yield of variable quality. Consideration of these factors is particularly important for single-cell and single-nuclei resolution transcriptomics due to the necessity for unbiased and representative cell or nuclei populations. Different cell, nuclei, and RNA extraction methods, library preparation, and quality control methods are used by the tendon research community and attention should be paid to these when designing and reporting studies. We discuss the different components and challenges of human tendon transcriptomics, and propose pipelines, quality control, and reporting guidelines for future work in the field.

The association between anterior shoulder joint capsule thickening and glenoid deformity in primary glenohumeral osteoarthritis.

BACKGROUND: Anterior shoulder joint capsule thickening is typically present in osteoarthritic shoulders, but its association with specific patterns of glenoid wear is incompletely understood. We sought to determine the relationship between anterior capsular thickening and glenoid deformity in primary glenohumeral osteoarthritis. METHODS: We retrospectively identified 134 consecutive osteoarthritic shoulders with magnetic resonance imaging and computed tomography scans performed. Axial fat-suppressed magnetic resonance imaging slices were used to quantify the anterior capsular thickness in millimeters, measured at its thickest point below the subscapularis muscle. Computed tomography scans were used to classify glenoid deformity according to the Walch classification, and an automated 3-dimensional software program provided values for glenoid retroversion and humeral head subluxation. Multinomial and linear regression models were used to characterize the association of anterior capsular thickening with Walch glenoid type, glenoid retroversion, and posterior humeral head subluxation while controlling for patient age and sex. RESULTS: The anterior capsule was thickest in glenoid types B2 (5.5 mm, 95% confidence interval [CI]: 5.0-6.0) and B3 (6.1 mm, 95% CI: 5.6-6.6) and thinnest in A1 (3.7 mm, 95% CI: 3.3-4.2; P < .001). Adjusted for age and sex, glenoid types B2 (odds ratio: 4.4, 95% CI: 2.3-8.4, P < .001) and B3 (odds ratio: 5.4, 95% CI: 2.8-10.4, P < .001) showed the strongest association with increased anterior capsule thickness, compared to glenoid type A1. Increased capsular thickness correlated with greater glenoid retroversion (r = 0.57; P < .001) and posterior humeral head subluxation (r = 0.50; P < .001). In multivariable analysis, for every 1-mm increase in anterior capsular thickening, there was an adjusted mean increase of 3.2° (95% CI: 2.4-4.1) in glenoid retroversion and a 3.8% (95% CI: 2.7-5.0) increase in posterior humeral head subluxation. CONCLUSIONS: Increased thickening of the anterior shoulder capsule is associated with greater posterior glenoid wear and humeral head subluxation. Additional research should determine whether anterior capsular disease plays a causative role in the etiology or progression of eccentric glenohumeral osteoarthritis.

Tendon and multiomics: advantages, advances, and opportunities.

Tendons heal by fibrosis, which hinders function and increases re-injury risk. Yet the biology that leads to degeneration and regeneration of tendons is not completely understood. Improved understanding of the metabolic nuances that cause diverse outcomes in tendinopathies is required to solve these problems. 'Omics methods are increasingly used to characterize phenotypes in tissues. Multiomics integrates 'omic datasets to identify coherent relationships and provide insight into differences in molecular and metabolic pathways between anatomic locations, and disease stages. This work reviews the current literature pertaining to multiomics in tendon and the potential of these platforms to improve tendon regeneration. We assessed the literature and identified areas where 'omics platforms contribute to the field: (1) Tendon biology where their hierarchical complexity and demographic factors are studied. (2) Tendon degeneration and healing, where comparisons across tendon pathologies are analyzed. (3) The in vitro engineered tendon phenotype, where we compare the engineered phenotype to relevant native tissues. (4) Finally, we review regenerative and therapeutic approaches. We identified gaps in current knowledge and opportunities for future study: (1) The need to increase the diversity of human subjects and cell sources. (2) Opportunities to improve understanding of tendon heterogeneity. (3) The need to use these improvements to inform new engineered and regenerative therapeutic approaches. (4) The need to increase understanding of the development of tendon pathology. Together, the expanding use of various 'omics platforms and data analysis resulting from these platforms could substantially contribute to major advances in the tendon tissue engineering and regenerative medicine field.

Biological resurfacing in a canine model of hip osteoarthritis.

Articular cartilage has unique load-bearing properties but has minimal capacity for intrinsic repair. Here, we used three-dimensional weaving, additive manufacturing, and autologous mesenchymal stem cells to create a tissue-engineered, bicomponent implant to restore hip function in a canine hip osteoarthritis model. This resorbable implant was specifically designed to function mechanically from the time of repair and to biologically integrate with native tissues for long-term restoration. A massive osteochondral lesion was created in the hip of skeletally mature hounds and repaired with the implant or left empty (control). Longitudinal outcome measures over 6 months demonstrated that the implant dogs returned to normal preoperative values of pain and function. Anatomical structure and functional biomechanical properties were also restored in the implanted dogs. Control animals never returned to normal and exhibited structurally deficient repair. This study provides clinically relevant evidence that the bicomponent implant may be a potential therapy for moderate hip osteoarthritis.

Transgenic conversion of ω-6 to ω-3 polyunsaturated fatty acids via fat-1 reduces the severity of post-traumatic osteoarthritis.

BACKGROUND: Dietary fatty acid (FA) content has been shown to influence the development of post-traumatic osteoarthritis (PTOA) in obesity. We used the fat-1 transgenic mouse to examine the hypothesis that endogenous reduction of ω-6 to ω-3 FA ratio, under the same dietary conditions, would mitigate metabolic inflammation and the pathogenesis of PTOA in obese male and female mice. METHODS: Male and female fat-1 and wild-type littermates were fed either a control diet or an ω-6 FA-rich high-fat diet and underwent destabilization of the medial meniscus (DMM) surgery to induce PTOA. OA severity, synovitis, and osteophyte formation were determined histologically, while biomarker and lipidomic analyses were performed to evaluate levels of adipokines, insulin, pro-/anti-inflammatory cytokines, and FAs in serum and joint synovial fluid. Multivariable models were performed to elucidate the associations of dietary, metabolic, and mechanical factors with PTOA. RESULTS: We found that elevated serum levels of ω-3 FAs in fat-1 mice as compared to wild-type controls fed the same diet resulted in reduced OA and synovitis in a sex- and diet-dependent manner, despite comparable body weights. The fat-1 mice showed trends toward decreased serum pro-inflammatory cytokines and increased anti-inflammatory cytokines. Multivariable analysis for variables predicting OA severity in mice resulted in correlations with serum FA levels, but not with body weight. CONCLUSIONS: This study provides further evidence that circulating FA composition and systemic metabolic inflammation, rather than body weight, may be the major risk factor for obesity-associated OA. We also demonstrate the potential genetic use of ω-3 FA desaturase in mitigating PTOA in obese patients following injury.

Contracture and transient receptor potential channel upregulation in the anterior glenohumeral joint capsule of patients with end-stage osteoarthritis.

BACKGROUND: During anatomic total shoulder arthroplasty (TSA) for primary glenohumeral osteoarthritis (GHOA), the anterior shoulder joint capsule (ASJC) is characterized grossly by contracture, synovitis, and fibrosis. In tissues that develop fibrosis, there is substantial cross-talk between macrophages, fibroblasts, and myofibroblasts, modulated by calcium signaling and transient receptor potential (TRP) channel signaling. The purpose of this study was to compare and characterize the degree of synovitis, inflammatory infiltrate, and TRP channel expression in ASJC harvested from shoulders with and without primary GHOA. METHODS: The ASJC was resected from patients undergoing TSA for primary GHOA or other diagnoses and compared with ASJC from cadaveric donors with no history of shoulder pathology. ASJC was evaluated by immunohistochemistry to characterize synovial lining and capsular inflammatory cell infiltrate and fibrosis, and to evaluate for expression of TRPA1, TRPV1, and TRPV4, known to be involved in fibrosis in other tissues. Blinded sections were evaluated by 3 graders using a semiquantitative scale; then results were compared between diagnosis groups using nonparametric methods. RESULTS: Compared with normal control, the ASJC in primary GHOA had significantly increased synovitis, fibrosis, mixed inflammatory cell infiltrate including multiple macrophages subsets, and upregulation of TRP channel expression. CONCLUSION: These data support the clinical findings of ASJC and synovial fibrosis in primary GHOA, identify a mixed inflammatory response, and identify dysregulation of TRP channels in the synovium and joint capsule. Further studies will identify the role of synovial and capsular fibrosis early in the development of GHOA.

Synthetic scaffolds for musculoskeletal tissue engineering: cellular responses to fiber parameters.

Tissue engineering often uses synthetic scaffolds to direct cell responses during engineered tissue development. Since cells reside within specific niches of the extracellular matrix, it is important to understand how the matrix guides cell response and then incorporate this knowledge into scaffold design. The goal of this review is to review elements of cell-matrix interactions that are critical to informing and evaluating cellular response on synthetic scaffolds. Therefore, this review examines fibrous proteins of the extracellular matrix and their effects on cell behavior, followed by a discussion of the cellular responses elicited by fiber diameter, alignment, and scaffold porosity of two dimensional (2D) and three dimensional (3D) synthetic scaffolds. Variations in fiber diameter, alignment, and scaffold porosity guide stem cells toward different lineages. Cells generally exhibit rounded morphology on nanofibers, randomly oriented fibers, and low-porosity scaffolds. Conversely, cells exhibit elongated, spindle-shaped morphology on microfibers, aligned fibers, and high-porosity scaffolds. Cells migrate with higher velocities on nanofibers, aligned fibers, and high-porosity scaffolds but migrate greater distances on microfibers, aligned fibers, and highly porous scaffolds. Incorporating relevant biomimetic factors into synthetic scaffolds destined for specific tissue application could take advantage of and further enhance these responses.

TRPV4-mediated calcium signaling in mesenchymal stem cells regulates aligned collagen matrix formation and vinculin tension.

Microarchitectural cues drive aligned fibrillar collagen deposition in vivo and in biomaterial scaffolds, but the cell-signaling events that underlie this process are not well understood. Utilizing a multicellular patterning model system that allows for observation of intracellular signaling events during collagen matrix assembly, we investigated the role of calcium (Ca2+) signaling in human mesenchymal stem cells (MSCs) during this process. We observed spontaneous Ca2+ oscillations in MSCs during fibrillar collagen assembly, and hypothesized that the transient receptor potential vanilloid 4 (TRPV4) ion channel, a mechanosensitive Ca2+-permeable channel, may regulate this signaling. Inhibition of TRPV4 nearly abolished Ca2+ signaling at initial stages of collagen matrix assembly, while at later times had reduced but significant effects. Importantly, blocking TRPV4 activity dramatically reduced aligned collagen fibril assembly; conversely, activating TRPV4 accelerated aligned collagen formation. TRPV4-dependent Ca2+ oscillations were found to be independent of pattern shape or subpattern cell location, suggesting this signaling mechanism is necessary for aligned collagen formation but not sufficient in the absence of physical (microarchitectural) cues that force multicellular alignment. As cell-generated mechanical forces are known to be critical to the matrix assembly process, we examined the role of TRPV4-mediated Ca2+ signaling in force generated across the load-bearing focal adhesion protein vinculin within MSCs using an FRET-based tension sensor. Inhibiting TRPV4 decreased tensile force across vinculin, whereas TRPV4 activation caused a dynamic unloading and reloading of vinculin. Together, these findings suggest TRPV4 activity regulates forces at cell-matrix adhesions and is critical to aligned collagen matrix assembly by MSCs.

Maternal Death and Its Investigation.

Maternal deaths are a leading cause of death in young females worldwide, particularly in developing countries. Maternal mortality ratio, the number of maternal deaths per 100 000 live births, averages 240 in developing regions, but only 16 in developed regions. Causes of maternal and pregnancy-related deaths can be subdivided into three broad categories. Direct maternal deaths result from obstetric complications of the pregnant state (i.e., pregnancy, labor, and puerperium) from interventions, omissions, incorrect treatment, or from a chain of events resulting from any of the above. Indirect maternal deaths result from previously existing diseases or diseases that developed during pregnancy, and which are not due to a direct obstetric cause, but are aggravated by the physiologic effects of pregnancy. Incidental maternal deaths are those from causes unrelated to pregnancy or the puerperium, including accidental deaths and homicide. Maternal deaths carry significant short- and long-term impacts for family members and the role of the pathologist is an important part of the wider knowledge-gathering process that can contribute to changes in maternal mortality rates. This paper reviews the clinical and pathological features of common pregnancy-related disorders and gives guidelines for performing an autopsy related to maternal death.

* Meltblown Polymer Fabrics as Candidate Scaffolds for Rotator Cuff Tendon Tissue Engineering.

Various biomaterial technologies are promising for tissue engineering, including electrospinning, but commercial scale-up of throughput is difficult. The goal of the study was to evaluate meltblown fabrics as candidate scaffolds for rotator cuff tendon tissue engineering. Meltblown poly(lactic acid) fabrics were produced with several polymer crystallinities and airflow velocities [500(low), 900(medium) or 1400(high) m3air/h/m fabric]. Fiber diameter, alignment, and baseline bidirectional tensile mechanical properties were evaluated. Attachment and spreading of human adipose-derived stem cells (hASCs) were evaluated over 3 days immediately following seeding. After initial screening, the fabric with the greatest Young's modulus and yield stress was selected for 28-day in vitro culture and for evaluation of tendon-like extracellular matrix production and development of mechanical properties. As expected, airflow velocity of the polymer during meltblowing demonstrated an inverse relationship with fiber diameter. All fabrics exhibited fiber alignment parallel to the direction of collector rotation. All fabrics demonstrated mechanical anisotropy at baseline. Cells attached, proliferated, and spread on all fabrics over the initial three-day culture period. Consistent with the observed loss of integrity of the unseeded biomaterial, hASC-seeded scaffolds demonstrated a significant decrease in Young's modulus over 28 days of culture. However, dsDNA, sulfated glycosaminoglycan, and collagen content increased significantly over 28 days. Histology and polarized light microscopy demonstrated collagen deposition and alignment throughout the thickness of the scaffolds. While fiber diameters approximated an order of magnitude greater than those previously reported for electrospun scaffolds intended for tendon tissue engineering, they were still within the range of collagen fiber diameters found in healthy tendon. The extent of matrix production and alignment was similar to that previously observed for multilayered electrospun scaffolds. While the Young's modulus of scaffolds after 28 days of culture was lower than native rotator cuff tendon, it approximated that reported previously following culture of electrospun scaffolds and was on the same order of magnitude as of current Food and Drug Administration-approved patches for rotator cuff augmentation. Together, these data suggest that with minor polymer and parameter modifications, meltblown scaffolds could provide an economical, high-throughput production alternative method to electrospinning for use in rotator cuff tendon tissue engineering.

Conditional Macrophage Depletion Increases Inflammation and Does Not Inhibit the Development of Osteoarthritis in Obese Macrophage Fas-Induced Apoptosis-Transgenic Mice.

OBJECTIVE: To investigate whether short-term, systemic depletion of macrophages can mitigate osteoarthritis (OA) following injury in the setting of obesity. METHODS: CSF-1R-GFP+ macrophage Fas-induced apoptosis (MaFIA)-transgenic mice that allow conditional depletion of macrophages were placed on a high-fat diet and underwent surgery to induce knee OA. A small molecule (AP20187) was administrated to deplete macrophages in MaFIA mice. The effects of macrophage depletion on acute joint inflammation, OA severity, and arthritic bone changes were evaluated using histology and micro-computed tomography. Immunohistochemical analysis was performed to identify various immune cells. The levels of serum and synovial fluid cytokines were also measured. RESULTS: Macrophage-depleted mice had significantly fewer M1 and M2 macrophages in the surgically operated joints relative to controls and exhibited decreased osteophyte formation immediately following depletion. Surprisingly, macrophage depletion did not attenuate the severity of OA in obese mice; instead, it induced systemic inflammation and led to a massive infiltration of CD3+ T cells and particularly neutrophils, but not B cells, into the injured joints. Macrophage-depleted mice also demonstrated a markedly increased number of proinflammatory cytokines including granulocyte colony-stimulating factor, interleukin-1ß (IL-1ß), IL-6, IL-8, and tumor necrosis factor in both serum and joint synovial fluid, although the mice showed a trend toward decreased levels of insulin and leptin in serum after macrophage depletion. CONCLUSION: Our findings indicate that macrophages are vital for modulating homeostasis of immune cells in the setting of obesity and suggest that more targeted approaches of depleting specific macrophage subtypes may be necessary to mitigate inflammation and OA in the setting of obesity.

Serum and synovial fluid lipidomic profiles predict obesity-associated osteoarthritis, synovitis, and wound repair.

High-fat diet-induced obesity is a major risk factor for osteoarthritis (OA) and diminished wound healing. The objective of this study was to determine the associations among serum and synovial fluid lipid levels with OA, synovitis, adipokine levels, and wound healing in a pre-clinical obese mouse model of OA. Male C57BL/6 J mice were fed either a low-fat (10% kcal) or one of three high-fat (HF, 60% kcal) diets rich in saturated fatty acids (SFAs), ω-6 or ω-3 polyunsaturated FAs (PUFAs). OA was induced by destabilization of the medial meniscus. Mice also received an ear punch for evaluating wound healing. Serum and synovial fluid were collected for lipidomic and adipokine analyses. We demonstrated that the serum levels of ω-3 PUFAs were negatively correlated with OA and wound size, but positively correlated with adiponectin levels. In contrast, most ω-6 PUFAs exhibited positive correlations with OA, impaired healing, and inflammatory adipokines. Interestingly, levels of pentadecylic acid (C15:0, an odd-chain SFA) and palmitoleic acid were inversely correlated with joint degradation. This study extends our understanding of the links of FAs with OA, synovitis and wound healing, and reports newly identified serum and synovial fluid FAs as predictive biomarkers of OA in obesity.

Functional outcome measures in a surgical model of hip osteoarthritis in dogs.

BACKGROUND: The hip is one of the most common sites of osteoarthritis in the body, second only to the knee in prevalence. However, current animal models of hip osteoarthritis have not been assessed using many of the functional outcome measures used in orthopaedics, a characteristic that could increase their utility in the evaluation of therapeutic interventions. The canine hip shares similarities with the human hip, and functional outcome measures are well documented in veterinary medicine, providing a baseline for pre-clinical evaluation of therapeutic strategies for the treatment of hip osteoarthritis. The purpose of this study was to evaluate a surgical model of hip osteoarthritis in a large laboratory animal model and to evaluate functional and end-point outcome measures. METHODS: Seven dogs were subjected to partial surgical debridement of cartilage from one femoral head. Pre- and postoperative pain and functional scores, gait analysis, radiographs, accelerometry, goniometry and limb circumference were evaluated through a 20-week recovery period, followed by histological evaluation of cartilage and synovium. RESULTS: Animals developed histological and radiographic evidence of osteoarthritis, which was correlated with measurable functional impairment. For example, Mankin scores in operated limbs were positively correlated to radiographic scores but negatively correlated to range of motion, limb circumference and 20-week peak vertical force. CONCLUSIONS: This study demonstrates that multiple relevant functional outcome measures can be used successfully in a large laboratory animal model of hip osteoarthritis. These measures could be used to evaluate relative efficacy of therapeutic interventions relevant to human clinical care.