Cartilages are unique in the family of connective tissues in that they contain a high concentration of the glycosaminoglycans, chondroitin sulfate and keratan sulfate attached to the core protein of the proteoglycan, aggrecan. Multiple aggrecan molecules are organized in the extracellular matrix via a domain-specific molecular interaction with hyaluronan and a link protein, and these high molecular weight aggregates are immobilized within the collagen and glycoprotein network. The high negative charge density of glycosaminoglycans provides hydrophilicity, high osmotic swelling pressure and conformational flexibility, which together function to absorb fluctuations in biomechanical stresses on cartilage during movement of an articular joint. We have summarized information on the history and current knowledge obtained by biochemical and genetic approaches, on cell-mediated regulation of aggrecan metabolism and its role in skeletal development, growth as well as during the development of joint disease. In addition, we describe the pathways for hyaluronan metabolism, with particular focus on the role as a "metabolic rheostat" during chondrocyte responses in cartilage remodeling in growth and disease. Future advances in effective therapeutic targeting of cartilage loss during osteoarthritic diseases of the joint as an organ as well as in cartilage tissue engineering would benefit from `big data' approaches and bioinformatics, to uncover novel feed-forward and feed-back mechanisms for regulating transcription and translation of genes and their integration into cell-specific pathways.

ABSTRACTThe deposition of aggrecan/hyaluronan (HA)‐rich matrix within the tendon body and surrounding peritenon impede tendon healing and result in compromised biomechanical properties. Hence, the development of novel strategies to achieve targeted removal of the aggrecan‐HA pericellular matrix may be effective in treating tendinopathy. The current study examined the therapeutic potential of a recombinant human hyaluronidase, rHuPH20 (FDA approved for reducing HA accumulation in tumors) for treating murine Achilles tendinopathy. The 12‐week‐old C57Bl/6 male mice were injected with two doses of rHuTGF‐β1 into the retrocalcaneal bursa (RCB) to induce a combined bursitis and tendinopathy. Twenty‐four hours following induction of injury, treatment groups were administered rHuPH20 Hyaluronidase (rHuPH20; Halozyme Therapeutics) into the RCB. At either 6 h (acute), 9 days, or 25 days following hyaluronidase treatment, Achilles tendons were analyzed for gene expression, histology and immunohistochemistry, fluorophore‐assisted carbohydrate electrophoresis, and biomechanical properties. The rHuPH20 treatment was effective, particularly at the acute and 9‐day time points, in (a) removing HA deposits from the Achilles tendon and surrounding tissues, (b) improving biomechanical properties of the healing tendon, and (c) eliciting targeted increases in expression of specific cell fate, extracellular matrix metabolism, and inflammatory genes. The potential of rHuPH20 to effectively clear the pro‐inflammatory, HA‐rich matrix within the RCB and tendon strongly supports the future refinement of injectable glycosidase preparations as potential treatments to protect or regenerate tendon tissue by reducing inflammation and scarring in the presence of bursitis or other inducers of damage such as mechanical overuse. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:59–69, 2020

The TTR (transforming growth factor β1 (TGFβ1) injection with treadmill running) model of murine joint injury was used to examine effects of intra-articular Hyaluronan (IA HA) on the metabolism of subchondral bone. HA was injected 24 h after TGFβ1 injection and its effects on the mRNA of 80 genes in the Nfkb pathway, and bone remodeling genes, Acp5, Nos2 and Arg1, in femoral and tibial epiphyses/metaphyses of injected and contralateral legs was assessed. Structural bone parameters at those sites were determined by Micro-computed tomography (micro CT) and bone remodeling cells identified with histochemistry for tartrate-resistant acid phosphatase and immunohistochemistry for Nitric oxide synthase 2 (NOS2) and Arginase 1. Gene expression responses in femoral compartments were generally inhibitory and notably biphasic whereas the tibia was relatively non-responsive. Gene expression was also altered in the contralateral femoral compartment but were predominantly activated. IA TGFb did not alter bone structure in the injected leg, but resulted in a statistically significant reduction (25-40%) in trabecular bone of the contralateral limb. IA HA did not affect such changes. This bone loss was associated with an acute decrease in transcript abundance for Acp5, Nos2, Arg1 and this decrease persisted for Nos2 and Arg1. In conclusion, the data illustrate that in this model, IA TGFβ1 injection results in marked biphasic changes in NfKb-regulated apoptosis, IL1 and IL12 pathways, which were transiently altered after IA HA therapy. The finding that all modulations are essentially restricted to the femoral compartment is consistent with the predominant localization and clearance of injected HA from this site.

Fibrillar collagens are highly prevalent in the extracellular matrix of all connective tissues and therefore commonly used as a biomaterial in tissue engineering applications. In the native environment, collagen fibers are arranged in a complex hierarchical structure that is often difficult to recreate in a tissue engineered construct. Small leucine rich proteoglycans as well as hyaluronan binding proteoglycans, aggrecan and versican, have been implicated in regulating fiber formation. In this study, we modified proteoglycan production in vitro by altering culture medium glucose concentrations (4500, 1000, 500, 250, and 125 mg/L), and evaluated its effect on the formation of collagen fibers inside tissue engineered meniscal constructs. Reduction of extracellular glucose resulted in a dose dependent decrease in total sulfated glycosaminoglycan (GAG) production, but minimal decreases of decorin and biglycan. However, fibromodulin doubled in production between 125 and 4500 mg/L glucose concentration. A peak in fiber formation was observed at 500 mg/L glucose concentration and corresponded with reductions in total GAG production. Fiber formation reduction at 125 and 250 mg/L glucose concentrations are likely due to changes in metabolic activity associated with a limited supply of glucose. These results point to proteoglycan production as a means to manipulate fiber architecture in tissue engineered constructs. STATEMENT OF SIGNIFICANCE: Fibrillar collagens are highly prevalent in the extracellular matrix of all connective tissues; however achieving appropriate assembly and organization of collagen fibers in engineered connective tissues is a persistent challenge. Proteoglycans have been implicated in regulating collagen fiber organization both in vivo and in vitro, however little is known about methods to control proteoglycan production and the subsequent fiber organization in tissue engineered menisci. Here, we show that media glucose content can be optimized to control proteoglycan production and collagen fiber assembly, with optimal collagen fiber assembly occurring at sub-physiologic levels of glucose.

ABSTRACTHyaluronan (HA), a high molecular weight non‐sulfated glycosaminoglycan, is an integral component of the extracellular matrix of developing and mature connective tissues including tendon. There are few published reports quantifying HA content during tendon growth and maturation, or detailing its effects on the mechanical properties of the tendon extracellular matrix. Therefore, the goal of the current study was to examine the role of HA synthesis during post‐natal skeletal growth and maturation, and its influence on tendon structure and biomechanical function. For this purpose, the morphological, biochemical, and mechanical properties of Achilles tendons from wild type (WT) and hyaluronan synthase 1 and 3 deficient mouse strains (Has1−/−(Has1KO),Has3−/−(Has3KO), andHas1−/−3−/−(Has1/3KO)) were determined at 4, 8, and 12 weeks of age. Overall, HAS‐deficient mice did not show any marked differences from WT mice in Achilles tendon morphology or in the HA and chondroitin/dermatan sulfate (CS/DS) contents. However,HAS1‐deficiency (in the single or Has1/3 double KO) impeded post‐natal formation of the retrocalcaneal bursa, implicating HAS1 in regulating HA metabolism by cells lining the bursal cavity. Together, these data suggest that HA metabolism via HAS1 and HAS3 does not markedly influence the extracellular matrix structure or function of the tendon body, but plays a role in the formation/maintenance of peritendinous bursa. Additional studies are warranted to elucidate the relationship of HA and CS/DS metabolism to tendon healing and repair in vivo. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2622–2632, 2018.

Purpose/Aim of the study: Healthy tendons are maintained in homeostasis through controlled usage of glucose for energy and redox equilibrium. Tendon cell stress imposed by overuse injury or vascular insufficiency is accompanied by activation of wound healing pathways which facilitate an adaptive response and the restoration of homeostasis. To understand this response at the gene expression level we have studied the in vivo effects of injected TGF-β1 in a murine model of tendinopathy, as well as treatment of murine tendon explants with either TGF-β1 or hypoxia in vitro. Methods and Results: We provide evidence (from expression patterns and immunohistochemistry) that both in vivo and in vitro, the stress response in tendon cells may be metabolically controlled in part by glycolytic reprogramming. A major feature of the response to TGF-β1 or hypoxia is activation of the Warburg pathway which generates lactate from glucose under normoxia and thereby inhibits mitochondrial energy production. Conclusions: We discuss the likely outcome of this major metabolic shift in terms of the potential benefits and damage to tendon and suggest how incorporation of this metabolic response into our understanding of initiation and progression of tendinopathies may offer new opportunities for diagnosis and the monitoring of therapies.

Background: The attempted healing of tendon after acute injury (overloading, partial tear or complete rupture) proceeds via the normal wound healing cascade involving hemostasis, inflammation, matrix synthesis and matrix remodeling. Depending on the degree of trauma and the nature of the post-injury milieu, a variable degree of healing and recovery of function occurs. Post-injury analgesia is often achieved with NSAIDs such as Ibuprofen, however there is increasing evidence that NSAID usage may interfere with the healing process. This study aimed to investigate the cellular mechanism by which IBU therapy might lead to a worsening of tendon pathology. Methods: We have examined the effect of oral Ibuprofen, on Achilles tendon healing in a TGFb1-induced murine tendinopathy model. Dosing was started 3 days after initial injury (acute cellular response phase) and continued for 22 days or started at 9 days after injury (transition to matrix regeneration phase) and given for 16 days. Cellular changes in tendon and surrounding peritenon were assessed using Hematoxylin/Eosin, chondroid accumulation with Safranin O and anti-aggrecan immunohistochemistry, and neo-vessel formation with GSI Lectin histochemistry. Markers of inflammation included histochemical localization of hyaluronan, immunohistochemistry of heavy chain 1 and TNFα-stimulated glycoprotein-6 (TSG6). Cell responses were further examined by RT-qPCR of 84 NFκB target genes and 84 wound healing genes. Biomechanical properties of tendons were evaluated by tensile testing. Results: At a clinically-relevant dosage, Ibuprofen prevented the process of remodeling/removal of the inflammatory matrix components, hyaluronan, HC1 and TSG6. Furthermore, the aberrant matrix remodeling was accompanied by activation at day 28 of genes (Col1a2, Col5a3, Plat, Ccl12, Itga4, Stat3, Vegfa, Mif, Col4a1, Rhoa, Relb, F8, Cxcl9, Lta, Ltb, Ccl12, Cdkn1a, Ccl22, Sele, Cd80), which were not activated at any time without the drug, and so appear most likely to be involved in the pathology. Of these, Vegfa, Col4a1, F8, Cxcl9 and Sele, have been shown to play a role in vascular remodeling, consistent with the appearance at 25 days of vasculogenic cell groups in the peritenon and fat pad stroma surrounding the Achilles of the drug-dosed mice. Tensile stiffness (p = 0.004) and elastic modulus (p = 0.012) were both decreased (relative to age-matched uninjured and non-dosed mice) in mice dosed with Ibuprofen from day 3 to day 25, whether injured or not. Conclusion: We conclude that the use of Ibuprofen for pain relief during inflammatory phases of tendinopathy, might interfere with the normal processes of extracellular matrix remodeling and cellular control of expression of inflammatory and wound healing genes. It is proposed that the known COX2-mediated anti-inflammatory effect of ibuprofen has detrimental effects on the turnover of a pro-inflammatory HA matrix produced in response to soft-tissue injury, thus preventing the switch to cellular responses associated with functional matrix remodeling and eventual healing.

We have used a murine Achilles tendinopathy model to investigate whether tissue changes (such as collagen disorganization, chondroid metaplasia, and loss of tensile properties) which are broadly characteristic of human tendinopathies, are accompanied by changes in the expression of chromatin-modifying enzymes and the methylation status of promoter regions of tendon cell DNA. Tendinopathy was induced by two intra-tendinous TGF-β1 injections followed by cage activity or treadmill running for up to 28 days. Activation of DNA methyltransferases occurred at 3 days after the TGF-β1 injections and also at 14 days, but only with treadmill activity. Genome-wide Methyl Mini-Seq™ analysis identified 19 genes with differentially methylated promoters, five of which perform functions with an apparent direct relevance to tendinopathy (Leprel2, Foxf1, Mmp25, Igfbp6, and Peg12). The functions of the genes identified included collagen fiber assembly and pericellular interactions, therefore their perturbation could play a role in the characteristic disorganization of fibers in affected tendons. We postulate that a study of the functional genomics of these genes in animal and human tendon could further delineate the pathogenesis of this multi-factorial complex disease. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:947-955, 2017.

INTRODUCTION: The meniscus is a fibrocartilaginous tissue, mainly consisting of water and collagen with small portions of proteoglycans. The large diameter circumferential collagen fibers interconnected by radially oriented tie fibers give rise to the stable mechanical properties of the meniscus which plays a role in load distribution and stability of the knee. Therefore, it is crucial to mimic the native meniscal fiber structure in the tissue engineered meniscus. Although glycosaminoglycans (GAGs) are known to support the collagen fiber structure, it has been shown that reducing chondroitin and dermatan sulfate GAG chains using chondroitinase ABC results in the enhancement of tensile strength and fiber production. Furthermore, we found that there is a negative correlation between the fiber diameter and the amount of GAGs. In addition, small leucine-rich proteoglycans (SLRPs) composed of protein-substituted GAGs have been shown specifically to be closely associated with the collagen fiber formation. Biglycan, decorin, and fibromodulin have multiple binding sites for collagen with high affinity, and their absence resulted in abnormal fiber formation while their abundance inhibited fibrillogenesis. Adipose-derived stem cells have been shown to increase the production of GAGs in response to an increase in glucose concentration, yet how fibrochondrocytes (FCCs) and mesenchymal stem cells (MSCs) react to a change in glucose concentration and its potential influence on fiber formation has not been studied. Thus, the objective of this work was to investigate the relationships between the glucose concentration of culture media, the production of SLRPs and the resultant fiber formation.

The superficial layers (surface and sub-surface) of human articular cartilage represent specialized joint tissues with cellular and matrix compositions different to the deeper layers. The distinct properties of the superficial layers confer specialized functions and also provide a frontline barrier to degenerative insult (cellular, soluble, biomechanical) from the joint space. The design of interventions to protect/regenerate the superficial layers in the earliest stages of joint pathology will require that the details of cellular phenotype and matrix turnover in this location are more fully understood. In normal human joints (Grade 0), single cells in the surface layer, and the next 2–3 cell layers (down to about 20 μm) appear fibroblast-like and flattened parallel to the surface, unlike deeper cells (20–200 μm from surface), which are more oval and can be present in small groups.

Equine degenerative suspensory ligament desmitis (DSLD) in Peruvian Paso horses typically presents at 7-15 years and is characterized by lameness, focal disorganization of collagen fibrils, and chondroid deposition in the body of the ligament. With the aim of developing a test for disease risk (that can be used to screen horses before breeding) we have quantified the expression of 76 TGFβ-signaling target genes in adipose-derived stromal fibroblasts (ADSCs) from six DSLD-affected and five unaffected Paso horses. Remarkably, 35 of the genes showed lower expression (p<0.05) in cells from DSLD-affected animals and this differential was largely eliminated by addition of exogenous TGFβ1. Moreover, TGFβ1-mediated effects on expression were prevented by the TGFβR1/2 inhibitor LY2109761, showing that the signaling was via a TGFβR1/2 complex. The genes affected by the pathology indicate that it is associated with a generalized metabolic disturbance, since some of those most markedly altered in DSLD cells (ATF3, MAPK14, ACVRL1 (ALK1), SMAD6, FOS, CREBBP, NFKBIA, and TGFBR2) represent master-regulators in a wide range of cellular metabolic responses.

Objective: Articular cartilage defects commonly result from traumatic injury and predispose to degenerative joint diseases. To test the hypothesis that aberrant healing responses and chronic inflammation lead to osteoarthritis (OA), we examined spatiotemporal changes in joint tissues after cartilage injury in murine knees. Since intra-articular injection of hyaluronan (HA) can attenuate injury-induced osteoarthritis in wild-type (WT) mice, we investigated a role for HA in the response to cartilage injury in mice lacking HA synthase 1 (Has1(-/-)).Design: Femoral groove cartilage of WT and Has1(-/-) mice was debrided to generate a non-bleeding wound. Macroscopic imaging, histology, and gene expression were used to evaluate naive, sham-operated, and injured joints.Results: Acute responses (1-2 weeks) in injured joints from WT mice included synovial hyperplasia with HA deposition and joint-wide increases in expression of genes associated with inflammation, fibrosis, and extracellular matrix (ECM) production. By 4 weeks, some resurfacing of damaged cartilage occurred, and early cell responses were normalized. Cartilage damage in Has1(-/-) mice also induced early responses; however, at 4 weeks, inflammation and fibrosis genes remained elevated with widespread cartilage degeneration and fibrotic scarring in the synovium and joint capsule.Conclusions: We conclude that the ineffective repair of injured cartilage in Has1(-/-) joints can be at least partly explained by the markedly enhanced expression of particular genes in pathways linked to ECM turnover, IL-17/IL-6 cytokine signaling, and apoptosis. Notably, Has1 ablation does not alter gross HA content in the ECM, suggesting that HAS1 has a unique function in the metabolism of inflammatory HA matrices. (C) 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

There exists a range of surgical and non-surgical approaches to the treatment of both acute and chronic tendon injuries. Despite surgical advances in the management of acute tears and increasing treatment options for tendinopathies, strategies frequently are unsuccessful, due to impaired mechanical properties of the treated tendon and/or a deficiency in progenitor cell activities. Hence, there is an urgent need for effective therapeutic strategies to augment intrinsic and/or surgical repair. Such approaches can benefit both tendinopathies and tendon tears which, due to their severity, appear to be irreversible or irreparable. Biologic therapies include the utilization of scaffolds as well as gene, growth factor, and cell delivery. These treatment modalities aim to provide mechanical durability or augment the biologic healing potential of the repaired tissue. Here, we review the emerging concepts and scientific evidence which provide a rationale for tissue engineering and regeneration strategies as well as discuss the clinical translation of recent innovations.

A major objective of this article is to examine the research implications of recently available genome-wide expression profiles of cartilage from human osteoarthritis (OA) joints. We propose that, when viewed in the light of extensive earlier work, this novel data provides a unique opportunity to reorient the design of experimental systems toward clinical relevance. Specifically, in the area of cartilage explant biology, this will require a fresh evaluation of existing paradigms, so as to optimize the choices of tissue source, cytokine/growth factor/nutrient addition, and biomechanical environment for discovery. Within this context, we firstly discuss the literature on the nature and role of potential catabolic mediators in OA pathology, including data from human OA cartilage, animal models of OA, and ex vivo studies. Secondly, due to the number and breadth of studies on IL-1β in this area, a major focus of the article is a critical analysis of the design and interpretation of cartilage studies where IL-1β has been used as a model cytokine. Thirdly, the article provides a data-driven perspective (including genome-wide analysis of clinical samples, studies on mutant mice, and clinical trials), which concludes that IL-1β should be replaced by soluble mediators such as IL-17 or TGF-β1, which are much more likely to mimic the disease in OA model systems. We also discuss the evidence that changes in early OA can be attributed to the activity of such soluble mediators, whereas late-stage disease results more from a chronic biomechanical effect on the matrix and cells of the remaining cartilage and on other local mediator-secreting cells. Lastly, an updated protocol for in vitro studies with cartilage explants and chondrocytes (including the use of specific gene expression arrays) is provided to motivate more disease-relevant studies on the interplay of cytokines, growth factors, and biomechanics on cellular behavior.

ADAMTS5 (TS5), a member of the aggrecanase clade (TS1, 4, 5, 8, 9, 15) of ADAMTS-proteases, has been considered largely responsible for the proteolysis of the hyalectans, aggrecan (Acan) and versican (Vcan), in vivo. However, we have reported that ts5-knockout (KO) mice show joint protection after injury due to inhibition of synovial scarring and enhanced Acan deposition. Also, KO mice have an impaired wound healing phenotype in skin and tendons which is associated with Acan/Vcan-rich deposits at the wound sites. Moreover, the Acan and Vcan deposited was aggrecanase-cleaved, even in the absence of TS5. In this study, we have used adipose-derived stromal cell (ADSC) and epiphyseal chondrocyte cultures from wild type and KO mice to further study the role of TS5 in Acan and Vcan turnover. We have confirmed with both cell types that the aggrecanase-mediated degradation of these hyalectans is not due to TS5, but an aggrecanase which primarily cleaves them before they are secreted. We also provide data which suggests that TS5 protein functions to suppress glucose uptake in ADSCs and thereby inhibits the synthesis, and promotes the intracellular degradation of Acan and Vcan by an ADAMTS other than TS5. We propose that this apparently non-proteolytic role of TS5 explains its anti-chondrogenic and pro-fibrotic effects in murine models of wound repair. A possible role for TS5 in an endocytotic process, involving competitive interactions between TS5, LRP1 and GLUT4 is discussed.

The authors regret that references 137–180 were missing from the original article published. This caused citations within Table I to not be referenced and so Table I has been corrected and appears below, along with the missing references. The authors would like to apologise for any inconvenience caused.Table IWound healing mediators in dermal and joint tissues showing their source and major effects on cellular responsesFactorJoint tissue sourceJoint tissue repair responsesWound cell source [20–23]Wound healing responses [20–23]EGFSY[133]; OA SF[134]Chondrocyte proliferation; ion transport, decreased matrix productionP,M,FEpithelializationFGF-2SY[135–137]; AT[138]; OP[137]; OA SF[139–142]Anti-apoptotic; prochondrogenicM,EP,END,FAngiogenesisGranulation tissueECM productionTGFβ1CA[143]; SY[144]; OP[137, 145]; OA SF[47, 48]Pro-catabolic (MMP-13); chondrocyte hypertrophyP,M,EP,END,FEpithelialization,Granulation TissueFibroplasiaBMPsSY[152]; CA[146–148]; BO[149, 150]; OA SF[151]Prochondrogenic; OsteophytesSCHairfollicle formationPDGFCA[143]; SY[153, 154]; OA SF[47]Stimulates reparative responses in fibrochondrocytes; anti-hypertrophicP,M,FGranulation tissueFibroplasiaContractionVEGFCA[155–159,163]; SY[158–161], AT[138]; OA SF[47, 162]Delays reparative responses in meniscus and CAP,N,M,END,FAngiogenesisIL1βCA[143]; SY[180]; post ACLT SF[164–167]; OA SF[48, 167–170]CA and meniscal matrix degradationN,M,EPInflammationEpithelializationIL6CA[171, 172]; AT[138, 173]; PC[174]; Post ACL SF[164, 175]; OA SF[48, 169]CA matrix degradationN,M,EPInflammationEpithelializationTNFαCA[143]; SY[176]; AT[138]; Post ACLT SF[167,170,175, 177,178]; OA SF[48,168,169].CA matrix degradationN,M,EPInflammationEpithelializationAbbreviations: ACLT: Anterior cruciate ligament tear; AT: Adipose tissue; OP: Osteophyte; PC: Plasma Cells; END: endothelial cells; EP: epithelial cells; F: Fibroblasts; M: Macrophages; N: Neutrophils; P: Platelets. 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A recently developed murine model of tendinopathy, induced by TGF‐β1 injection, has been used to examine the reparative capacity of tendinopathic Achilles in Adamts5−/− mice. After TGF‐β1 injection and 2 weeks of treadmill exercise, the Achilles from Adamts5−/− mice exhibited a reduction in maximum tensile stress of approximately 60%. However, in contrast to wild type mice previously characterized by this model, Adamts5−/− mice subjected to further treadmill exercise were unable to reverse this biomechanical deficit. This nonreparative phenotype was accompanied by a major deficiency, relative to wild‐type, in expression of Col1a1 and Col3a1 and an abnormally elevated expression of a wide range of integrins. In addition, the tendinopathic Adamts5−/− mice showed a persistent accumulation of chondrogenic cells in the tendon body and an aggrecan‐rich fibrocartilaginous matrix within disorganized collagen fiber bundles. Moreover, consistent with the compromised biomechanical properties of the Achilles in the Adamts5−/− mice, in vivo gait analysis revealed a strong trend (p = 0.07) towards increased swing time of the injected limb in Adamts5−/− relative to wild‐type mice. These findings demonstrate that a deficiency in ADAMTS5 promotes a chondrogenic response to TGF‐β1 injection that is not reversed by treadmill exercise. Hence, repair of biomechanically compromised tendons exhibiting midsubstance chondroid accumulation requires ADAMTS5. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1540–1548, 2013