Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Post-traumatic osteoarthritis: from mouse models to clinical trials

Nature Reviews Rheumatology volume 9, pages 485–497 (2013)Cite this article

Subjects

Abstract

Osteoarthritis (OA), the most common of all arthropathies, is a leading cause of disability and has a large (and growing) worldwide socioeconomic cost. Despite its burgeoning importance, translation of disease-modifying OA therapies from the laboratory into clinical practice has slowed. Differences between the OA models studied preclinically and the disease evaluated in human clinical trials contribute to this failure. Most animal models of OA induce disease through surgical or mechanical disruption of joint biomechanics in young individuals rather than the spontaneous development of age-associated disease. This instability-induced joint disease in animals best models the arthritis that develops in humans after an injurious event, known as post-traumatic OA (PTOA). Studies in genetically modified mice suggest that PTOA has a distinct molecular pathophysiology compared with that of spontaneous OA, which might explain the poor translation from preclinical to clinical OA therapeutic trials. This Review summarizes the latest data on potential molecular targets for PTOA prevention and modification derived from studies in genetically modified mice, and describes their validation in preclinical therapeutic trials. This article focuses on how these findings might best be translated to humans, and identifies the potential challenges to successful implementation of clinical trials of disease-modifying drugs for PTOA.

Key Points

  • The translational value of animal models is primarily determined by how well they correspond with the human condition, and major improvements might be achieved by aligning preclinical and clinical disease

  • Preclinical research and drug development primarily uses models of post-traumatic osteoarthritis (OA) in young individuals; its molecular pathophysiology could be different than the age-associated OA most commonly targeted in clinical trials

  • Post-traumatic OA in mice is a valid model of the human disease, and using genetically engineered strains has identified disease-modifying targets that have been validated in preclinical therapeutic studies

  • Issues remain in study design for therapeutic clinical trials of post-traumatic OA, and the development of predictive biomarkers is critical to drug development for this common and costly disease

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Osteoarthritis is a global disease with pathological changes occurring in all the tissues of the joint.
Figure 2: Biochemical and biomechanical crosstalk between joint tissues might contribute to the onset and progression of joint pathology in post-traumatic osteoarthritis.

Similar content being viewed by others

References

  1. Pereira, D. et al. The effect of osteoarthritis definition on prevalence and incidence estimates: a systematic review. Osteoarthritis Cartilage 19, 1270–1285 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Access Economics. Painful realities: The economic impact of arthritis in Australia in 2007. Access Economics Report (2007).

  3. Matthews, G. L. & Hunter, D. J. Emerging drugs for osteoarthritis. Expert Opin. Emerg. Drugs 16, 479–491 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Zhang, W. et al. OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage 18, 476–499 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Australian Orthopaedic Association National Joint Replacement Registry. Annual Report 2011 [online], (2011).

  6. [No authors listed] Arthritis prevalence and activity limitations—United States, 1990. Morbidity & Mortality Weekly Report 43, 433–438 (1994).

  7. Aigner, T. & Richter, W. OA in 2011: Age-related OA—a concept emerging from infancy? Nat. Rev. Rheumatol. 8, 70–72 (2012).

    Article  PubMed  Google Scholar 

  8. Blanco, F. J., Rego, I. & Ruiz-Romero, C. The role of mitochondria in osteoarthritis. Nat. Rev. Rheumatol. 7, 161–169 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Heinegard, D. & Saxne, T. The role of the cartilage matrix in osteoarthritis. Nat. Rev. Rheumatol. 7, 50–56 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Kapoor, M., Martel-Pelletier, J., Lajeunesse, D., Pelletier, J. P. & Fahmi, H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat. Rev. Rheumatol. 7, 33–42 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Lories, R. J. & Luyten, F. P. The bone–cartilage unit in osteoarthritis. Nat. Rev. Rheumatol. 7, 43–49 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Lotz, M. K. & Carames, B. Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA. Nat. Rev. Rheumatol. 7, 579–587 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mease, P. J., Hanna, S., Frakes, E. P. & Altman, R. D. Pain mechanisms in osteoarthritis: understanding the role of central pain and current approaches to its treatment. J. Rheumatol. 38, 1546–1551 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Pitsillides, A. A. & Beier, F. Cartilage biology in osteoarthritis—lessons from developmental biology. Nat. Rev. Rheumatol. 7, 654–663 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Roos, E. M., Herzog, W., Block, J. A. & Bennell, K. L. Muscle weakness, afferent sensory dysfunction and exercise in knee osteoarthritis. Nat. Rev. Rheumatol. 7, 57–63 (2011).

    Article  PubMed  Google Scholar 

  16. Sandell, L. J. Etiology of osteoarthritis: genetics and synovial joint development. Nat. Rev. Rheumatol. 8, 77–89 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Sellam, J. & Berenbaum, F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol. 6, 625–635 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Sofat, N., Ejindu, V. & Kiely, P. What makes osteoarthritis painful? The evidence for local and central pain processing. Rheumatology (Oxford) 50, 2157–2165 (2011).

    Article  Google Scholar 

  19. Weinans, H. et al. Pathophysiology of peri-articular bone changes in osteoarthritis. Bone 51, 190–196 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Driban, J. B., Sitler, M. R., Barbe, M. F. & Balasubramanian, E. Is osteoarthritis a heterogeneous disease that can be stratified into subsets? Clin. Rheumatol. 29, 123–131 (2010).

    Article  PubMed  Google Scholar 

  21. Herrero-Beaumont, G., Roman-Blas, J. A., Castaneda, S. & Jimenez, S. A. Primary osteoarthritis no longer primary: three subsets with distinct etiological, clinical, and therapeutic characteristics. Semin. Arthritis Rheum. 39, 71–80 (2009).

    Article  PubMed  Google Scholar 

  22. McGonagle, D., Tan, A. L., Carey, J. & Benjamin, M. The anatomical basis for a novel classification of osteoarthritis and allied disorders. J. Anat. 216, 279–291 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lane, N. E. et al. OARSI-FDA initiative: defining the disease state of osteoarthritis. Osteoarthritis Cartilage 19, 478–482 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Bierma-Zeinstra, S. M. & Verhagen, A. P. Osteoarthritis subpopulations and implications for clinical trial design. Arthritis Res. Ther. 13, 213 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Little, C. B. & Fosang, A. J. Is cartilage matrix breakdown an appropriate therapeutic target in osteoarthritis—insights from studies of aggrecan and collagen proteolysis? Curr. Drug Targets 11, 561–575 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Little, C. B. & Zaki, S. What constitutes an “animal model of osteoarthritis”—the need for consensus? Osteoarthritis Cartilage 20, 261–267 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Aigner, T. et al. Histopathology atlas of animal model systems—overview of guiding principles. Osteoarthritis Cartilage 18 (Suppl. 3), S2–S6 (2010).

    Article  PubMed  Google Scholar 

  28. Little, C. Experimental Models of OA. OARSI Primer [online], (2011).

    Google Scholar 

  29. Little, C. B. & Smith, M. M. Animal models of osteoarthritis. Curr. Rheumatol. Rev. 4, 175–182 (2008).

    Article  CAS  Google Scholar 

  30. Smith, M. & Little, C. in Osteoarthitis: Diagnosis and Medical/Surgical Management (eds Moskowitz, R., Altman, R., Hochberg, M., Buckwalter, J. & Goldberg, V.) 107–125 (Lipincott Williams & Wilkins, 2007).

    Google Scholar 

  31. Hunter, D. J. Pharmacologic therapy for osteoarthritis—the era of disease modification. Nat. Rev. Rheumatol. 7, 13–22 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Reginster, J. Y. et al. Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial. Ann. Rheum. Dis. 72, 179–186 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Laupacis, A., Sackett, D. L. & Roberts, R. S. An assessment of clinically useful measures of the consequences of treatment. N. Engl. J. Med. 318, 1728–1733 (1988).

    Article  CAS  PubMed  Google Scholar 

  34. Christensen, P. M. & Kristiansen, I. S. Number-needed-to-treat (NNT)—needs treatment with care. Basic Clin. Pharmacol. Toxicol. 99, 12–16 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Lafeber, F. P. & van Laar, J. M. Strontium ranelate: ready for clinical use as disease-modifying osteoarthritis drug? Ann. Rheum. Dis. 72, 157–161 (2013).

    Article  PubMed  Google Scholar 

  36. Pelletier, J. P. et al. Strontium ranelate reduces the progression of experimental dog osteoarthritis by inhibiting the expression of key proteases in cartilage and of IL-1β in the synovium. Ann. Rheum. Dis. 72, 250–257 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Cooper, C. et al. Efficacy and safety of oral strontium ranelate for the treatment of knee osteoarthritis: rationale and design of randomised, double-blind, placebo-controlled trial. Curr. Med. Res. Opin. 28, 231–239 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Wehling, M. Assessing the translatability of drug projects: what needs to be scored to predict success? Nat. Rev. Drug Discov. 8, 541–546 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Wehling, M. Drug development in the light of translational science: shine or shade? Drug Discov. Today 16, 1076–1083 (2011).

    Article  PubMed  Google Scholar 

  40. Wendler, A. & Wehling, M. The translatability of animal models for clinical development: biomarkers and disease models. Curr. Opin. Pharmacol. 10, 601–606 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Cake, M. A. et al. Comparison of gait and pathology outcomes of three meniscal procedures for induction of knee osteoarthritis in sheep. Osteoarthritis Cartilage 21, 226–236 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Welch, I. D., Cowan, M. F., Beier, F. & Underhill, T. M. The retinoic acid binding protein CRABP2 is increased in murine models of degenerative joint disease. Arthritis Res. Ther. 11, R14 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. van Lent, P. L. et al. Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis. Arthritis Rheum. 64, 1466–1476 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Alexopoulos, L. G., Youn, I., Bonaldo, P. & Guilak, F. Developmental and osteoarthritic changes in Col6a1-knockout mice: biomechanics of type VI collagen in the cartilage pericellular matrix. Arthritis Rheum. 60, 771–779 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Christensen, S. E. et al. Altered trabecular bone structure and delayed cartilage degeneration in the knees of collagen VI null mice. PLoS ONE 7, e33397 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Altman, R. et al. The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip. Arthritis Rheum. 34, 505–514 (1991).

    Article  CAS  PubMed  Google Scholar 

  47. Altman, R. et al. The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hand. Arthritis Rheum. 33, 1601–1610 (1990).

    Article  CAS  PubMed  Google Scholar 

  48. Altman, R. et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum. 29, 1039–1049 (1986).

    Article  CAS  PubMed  Google Scholar 

  49. Altman, R. D. Classification of disease: osteoarthritis. Semin. Arthritis Rheum. 20, 40–47 (1991).

    Article  CAS  PubMed  Google Scholar 

  50. Luyten, F. P., Denti, M., Filardo, G., Kon, E. & Engebretsen, L. Definition and classification of early osteoarthritis of the knee. Knee Surg. Sports Traumatol. Arthrosc. 20, 401–406 (2012).

    Article  PubMed  Google Scholar 

  51. Pearson, R. G., Kurien, T., Shu, K. S. & Scammell, B. E. Histopathology grading systems for characterisation of human knee osteoarthritis—reproducibility, variability, reliability, correlation, and validity. Osteoarthritis Cartilage 19, 324–331 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Rout, R. et al. The histological features of anteromedial gonarthrosis—the comparison of two grading systems in a human phenotype of osteoarthritis. Knee 18, 172–176 (2011).

    Article  PubMed  Google Scholar 

  53. Anderson, D. D., Marsh, J. L. & Brown, T. D. The pathomechanical etiology of post-traumatic osteoarthritis following intraarticular fractures. Iowa Orthop. J. 31, 1–20 (2011).

    PubMed  PubMed Central  Google Scholar 

  54. Lotz, M. K. New developments in osteoarthritis. Posttraumatic osteoarthritis: pathogenesis and pharmacological treatment options. Arthritis Res. Ther. 12, 211 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Lawrence, R. C. et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 58, 26–35 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Brown, T. D., Johnston, R. C., Saltzman, C. L., Marsh, J. L. & Buckwalter, J. A. Posttraumatic osteoarthritis: a first estimate of incidence, prevalence, and burden of disease. J. Orthop. Trauma 20, 739–744 (2006).

    Article  PubMed  Google Scholar 

  57. Gelber, A. C. et al. Joint injury in young adults and risk for subsequent knee and hip osteoarthritis. Ann. Intern. Med. 133, 321–328 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Muthuri, S. G., McWilliams, D. F., Doherty, M. & Zhang, W. History of knee injuries and knee osteoarthritis: a meta-analysis of observational studies. Osteoarthritis Cartilage 19, 1286–1293 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Gelber, A. C. et al. Body mass index in young men and the risk of subsequent knee and hip osteoarthritis. Am. J. Med. 107, 542–548 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Lohmander, L. S., Englund, P. M., Dahl, L. L. & Roos, E. M. The long-term consequence of anterior cruciate ligament and meniscus injuries: osteoarthritis. Am. J. Sports Med. 35, 1756–1769 (2007).

    Article  PubMed  Google Scholar 

  61. Frobell, R. B., Lohmander, L. S. & Roos, H. P. Acute rotational trauma to the knee: poor agreement between clinical assessment and magnetic resonance imaging findings. Scand. J. Med. Sci. Sports 17, 109–114 (2007).

    CAS  PubMed  Google Scholar 

  62. Nielsen, A. B. & Yde, J. Epidemiology of acute knee injuries: a prospective hospital investigation. J. Trauma 31, 1644–1648 (1991).

    Article  CAS  PubMed  Google Scholar 

  63. Gage, B. E., McIlvain, N. M., Collins, C. L., Fields, S. K. & Comstock, R. D. Epidemiology of 6.6 million knee injuries presenting to United States emergency departments from 1999 through 2008. Acad. Emerg. Med. 19, 378–385 (2012).

    Article  PubMed  Google Scholar 

  64. Parkkari, J., Pasanen, K., Mattila, V. M., Kannus, P. & Rimpela, A. The risk for a cruciate ligament injury of the knee in adolescents and young adults: a population-based cohort study of 46,500 people with a 9 year follow-up. Br. J. Sports Med. 42, 422–426 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Lohmander, L. S., Ostenberg, A., Englund, M. & Roos, H. High prevalence of knee osteoarthritis, pain, and functional limitations in female soccer players twelve years after anterior cruciate ligament injury. Arthritis Rheum. 50, 3145–3152 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Neuman, P. et al. Prevalence of tibiofemoral osteoarthritis 15 years after nonoperative treatment of anterior cruciate ligament injury: a prospective cohort study. Am. J. Sports Med. 36, 1717–1725 (2008).

    Article  PubMed  Google Scholar 

  67. Roos, H., Adalberth, T., Dahlberg, L. & Lohmander, L. S. Osteoarthritis of the knee after injury to the anterior cruciate ligament or meniscus: the influence of time and age. Osteoarthritis Cartilage 3, 261–267 (1995).

    Article  CAS  PubMed  Google Scholar 

  68. Felson, D. T. et al. Osteoarthritis: new insights. Part 1: the disease and its risk factors. Ann. Intern. Med. 133, 635–646 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Felson, D. T. & Zhang, Y. An update on the epidemiology of knee and hip osteoarthritis with a view to prevention. Arthritis Rheum. 41, 1343–1355 (1998).

    Article  CAS  PubMed  Google Scholar 

  70. Hewett, T. E., Ford, K. R. & Myer, G. D. Anterior cruciate ligament injuries in female athletes: Part 2, a meta-analysis of neuromuscular interventions aimed at injury prevention. Am. J. Sports Med. 34, 490–498 (2006).

    Article  PubMed  Google Scholar 

  71. Yoo, J. H. et al. A meta-analysis of the effect of neuromuscular training on the prevention of the anterior cruciate ligament injury in female athletes. Knee Surg. Sports Traumatol. Arthrosc. 18, 824–830 (2010).

    Article  PubMed  Google Scholar 

  72. Finch, C. F. et al. Towards a national sports safety strategy: addressing facilitators and barriers towards safety guideline uptake. Inj. Prev. 17, e4 (2011).

    Article  PubMed  Google Scholar 

  73. Brophy, R. H., Wright, R. W. & Matava, M. J. Cost analysis of converting from single-bundle to double-bundle anterior cruciate ligament reconstruction. Am. J. Sports Med. 37, 683–687 (2009).

    Article  PubMed  Google Scholar 

  74. Gianotti, S. M., Marshall, S. W., Hume, P. A. & Bunt, L. Incidence of anterior cruciate ligament injury and other knee ligament injuries: a national population-based study. J. Sci. Med. Sport 12, 622–627 (2009).

    Article  PubMed  Google Scholar 

  75. Lubowitz, J. H. & Appleby, D. Cost-effectiveness analysis of the most common orthopaedic surgery procedures: knee arthroscopy and knee anterior cruciate ligament reconstruction. Arthroscopy 27, 1317–1322 (2011).

    Article  PubMed  Google Scholar 

  76. Yelin, E. & Callahan, L. F. The economic cost and social and psychological impact of musculoskeletal conditions. National Arthritis Data Work Groups. Arthritis Rheum. 38, 1351–1362 (1995).

    Article  CAS  PubMed  Google Scholar 

  77. Losina, E. et al. Impact of obesity and knee osteoarthritis on morbidity and mortality in older Americans. Ann. Intern. Med. 154, 217–226 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Anderson, D. D., Van Hofwegen, C., Marsh, J. L. & Brown, T. D. Is elevated contact stress predictive of post-traumatic osteoarthritis for imprecisely reduced tibial plafond fractures? J. Orthop. Res. 29, 33–39 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Marsh, J. L. et al. Articular fractures: does an anatomic reduction really change the result? J. Bone Joint Surg. Am. 84-A, 1259–1271 (2002).

    Article  CAS  Google Scholar 

  80. Anderson, D. D. et al. Intra-articular contact stress distributions at the ankle throughout stance phase-patient-specific finite element analysis as a metric of degeneration propensity. Biomech. Model Mechanobiol. 5, 82–89 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Anderson, D. D. et al. Post-traumatic osteoarthritis: improved understanding and opportunities for early intervention. J. Orthop. Res. 29, 802–809 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Thomas, T. P. et al. A computational/experimental platform for investigating three-dimensional puzzle solving of comminuted articular fractures. Comput. Methods Biomech. Biomed. Engin. 14, 263–270 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Frobell, R. B., Roos, E. M., Roos, H. P., Ranstam, J. & Lohmander, L. S. A randomized trial of treatment for acute anterior cruciate ligament tears. N. Engl. J. Med. 363, 331–342 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Delince, P. & Ghafil, D. Anterior cruciate ligament tears: conservative or surgical treatment? Knee Surg. Sports Traumatol. Arthrosc. (2012).

  85. Claes, S., Hermie, L., Verdonk, R., Bellemans, J. & Verdonk, P. Is osteoarthritis an inevitable consequence of anterior cruciate ligament reconstruction? A meta-analysis. Knee Surg. Sports Traumatol. Arthrosc. (2012).

  86. Streich, N. A., Zimmermann, D., Bode, G. & Schmitt, H. Reconstructive versus non-reconstructive treatment of anterior cruciate ligament insufficiency. A retrospective matched-pair long-term follow-up. Int. Orthop. 35, 607–613 (2011).

    Article  PubMed  Google Scholar 

  87. Meunier, A., Odensten, M. & Good, L. Long-term results after primary repair or non-surgical treatment of anterior cruciate ligament rupture: a randomized study with a 15-year follow-up. Scand. J. Med. Sci. Sports 17, 230–237 (2007).

    CAS  PubMed  Google Scholar 

  88. Englund, M., Roemer, F. W., Hayashi, D., Crema, M. D. & Guermazi, A. Meniscus pathology, osteoarthritis and the treatment controversy. Nat. Rev. Rheumatol. 8, 412–419 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Understanding Animal Research. Understanding animal research [online]

  90. Oh, H., Chun, C. H. & Chun, J. S. Dkk-1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice. Arthritis Rheum. 64, 2568–2578 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Kaneko, H. et al. Synovial perlecan is required for osteophyte formation in knee osteoarthritis. Matrix Biol. http://dx.doi.org/10.1016/j.matbio.2013.01.004.

  92. Miller, R. E. et al. CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis. Proc. Natl Acad. Sci. USA 109, 20602–20607 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Wendler, A. & Wehling, M. Translatability scoring in drug development: eight case studies. J. Transl. Med. 10, 39 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Jordan, J. M. et al. Methodologic issues in clinical trials for prevention or risk reduction in osteoarthritis. Osteoarthritis Cartilage 19, 500–508 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hunter, D. J. et al. A pathway and approach to biomarker validation and qualification for osteoarthritis clinical trials. Curr. Drug Targets 11, 536–545 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Spindler, K. P. et al. Prognosis and predictors of ACL reconstructions using the MOON cohort: a model for comparative effectiveness studies. J. Orthop. Res. 31, 2–9 (2013).

    Article  PubMed  Google Scholar 

  97. Wright, R. W. et al. Descriptive epidemiology of the Multicenter ACL Revision Study (MARS) cohort. Am. J. Sports Med. 38, 1979–1986 (2010).

    Article  PubMed  Google Scholar 

  98. Botter, S. M. et al. ADAMTS5−/− mice have less subchondral bone changes after induction of osteoarthritis through surgical instability: implications for a link between cartilage and subchondral bone changes. Osteoarthritis Cartilage 17, 636–645 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Glasson, S. S. et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434, 644–648 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Malfait, A. M. et al. ADAMTS-5 deficient mice do not develop mechanical allodynia associated with osteoarthritis following medial meniscal destabilization. Osteoarthritis Cartilage 18, 572–580 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Chockalingam, P. S. et al. Elevated aggrecanase activity in a rat model of joint injury is attenuated by an aggrecanase specific inhibitor. Osteoarthritis Cartilage 19, 315–323 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. Majumdar, M. K. et al. Double-knockout of ADAMTS-4 and ADAMTS-5 in mice results in physiologically normal animals and prevents the progression of osteoarthritis. Arthritis Rheum. 56, 3670–3674 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Little, C. B. et al. Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair. J. Clin. Invest. 117, 1627–1636 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wang, Q. et al. Identification of a central role for complement in osteoarthritis. Nat. Med. 17, 1674–1679 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Sondergaard, B. C. et al. Mice over-expressing salmon calcitonin have strongly attenuated osteoarthritic histopathological changes after destabilization of the medial meniscus. Osteoarthritis Cartilage 20, 136–143 (2012).

    Article  CAS  PubMed  Google Scholar 

  106. Manicourt, D. H. et al. Treatment with calcitonin suppresses the responses of bone, cartilage, and synovium in the early stages of canine experimental osteoarthritis and significantly reduces the severity of the cartilage lesions. Arthritis Rheum. 42, 1159–1167 (1999).

    Article  CAS  PubMed  Google Scholar 

  107. Nielsen, R. H., Bay-Jensen, A. C., Byrjalsen, I. & Karsdal, M. A. Oral salmon calcitonin reduces cartilage and bone pathology in an osteoarthritis rat model with increased subchondral bone turnover. Osteoarthritis Cartilage 19, 466–473 (2011).

    Article  CAS  PubMed  Google Scholar 

  108. El Hajjaji, H. et al. Treatment with calcitonin prevents the net loss of collagen, hyaluronan and proteoglycan aggregates from cartilage in the early stages of canine experimental osteoarthritis. Osteoarthritis Cartilage 12, 904–911 (2004).

    Article  PubMed  Google Scholar 

  109. Shen, P. C. et al. T helper cells promote disease progression of osteoarthritis by inducing macrophage inflammatory protein-1γ. Osteoarthritis Cartilage 19, 728–736 (2011).

    Article  PubMed  Google Scholar 

  110. Hirata, M. et al. C/EBPβ Promotes transition from proliferation to hypertrophic differentiation of chondrocytes through transactivation of p57. PLoS ONE 4, e4543 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kozawa, E. et al. Osteoarthritic change is delayed in a Ctsk-knockout mouse model of osteoarthritis. Arthritis Rheum. 64, 454–464 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. Connor, J. R. et al. Protective effects of a cathepsin K inhibitor, SB-553484, in the canine partial medial meniscectomy model of osteoarthritis. Osteoarthritis Cartilage 17, 1236–1243 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Hayami, T., Zhuo, Y., Wesolowski, G. A., Pickarski, M. & Duong Le, T. Inhibition of cathepsin K reduces cartilage degeneration in the anterior cruciate ligament transection rabbit and murine models of osteoarthritis. Bone 50, 1250–1259 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Xu, L. et al. Attenuation of osteoarthritis progression by reduction of discoidin domain receptor 2 in mice. Arthritis Rheum. 62, 2736–2744 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Saito, T. et al. Transcriptional regulation of endochondral ossification by HIF-2α during skeletal growth and osteoarthritis development. Nat. Med. 16, 678–686 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Yang, S. et al. Hypoxia-inducible factor-2α is a catabolic regulator of osteoarthritic cartilage destruction. Nat. Med. 16, 687–693 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Ryu, J. H. et al. Hypoxia-inducible factor-2α regulates Fas-mediated chondrocyte apoptosis during osteoarthritic cartilage destruction. Cell Death Differ. 19, 440–450 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Valverde-Franco, G. et al. In vivo bone-specific Ephb4 overexpression in mice protects both subchondral bone and cartilage during osteoarthritis. Arthritis Rheum. 64, 3614–3625 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. Amiable, N. et al. Proteinase-activated receptor-2 gene disruption limits the effect of osteoarthritis on cartilage in mice: a novel target in joint degradation. J. Rheumatol. 38, 911–920 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Ferrell, W. R., Kelso, E. B., Lockhart, J. C., Plevin, R. & McInnes, I. B. Protease-activated receptor 2: a novel pathogenic pathway in a murine model of osteoarthritis. Ann. Rheum. Dis. 69, 2051–2054 (2010).

    Article  PubMed  Google Scholar 

  121. Weng, T. et al. Genetic inhibition of FGFR1 in cartilage attenuates articular cartilage degeneration in adult mice. Arthritis Rheum. 64, 3982–3992 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Glasson, S. S. In vivo osteoarthritis target validation utilizing genetically-modified mice. Curr. Drug Targets 8, 367–376 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Caron, J. P. et al. Chondroprotective effect of intraarticular injections of interleukin-1 receptor antagonist in experimental osteoarthritis. Suppression of collagenase-1 expression. Arthritis Rheum. 39, 1535–1544 (1996).

    Article  CAS  PubMed  Google Scholar 

  124. Kadri, A. et al. Osteoprotegerin inhibits cartilage degradation through an effect on trabecular bone in murine experimental osteoarthritis. Arthritis Rheum. 58, 2379–2386 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Ryu, J. H. et al. Interleukin-6 plays an essential role in hypoxia-inducible factor 2α-induced experimental osteoarthritic cartilage destruction in mice. Arthritis Rheum. 63, 2732–2743 (2011).

    Article  CAS  PubMed  Google Scholar 

  126. Schmid, R. et al. Enhanced cartilage regeneration in MIA/CD-RAP deficient mice. Cell Death Dis. 1, e97 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Little, C. B. et al. Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum. 60, 3723–3733 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Johnson, A. R. et al. Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects. J. Biol. Chem. 282, 27781–27791 (2007).

    Article  CAS  PubMed  Google Scholar 

  129. Settle, S. et al. Cartilage degradation biomarkers predict efficacy of a novel, highly selective matrix metalloproteinase 13 inhibitor in a dog model of osteoarthritis: confirmation by multivariate analysis that modulation of type II collagen and aggrecan degradation peptides parallels pathologic changes. Arthritis Rheum. 62, 3006–3015 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Wang, M. et al. MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res. Ther. 15, R5 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ward, B. D. et al. Absence of posttraumatic arthritis following intraarticular fracture in the MRL/MpJ mouse. Arthritis Rheum. 58, 744–753 (2008).

    Article  PubMed  Google Scholar 

  132. Ruan, M. Z. et al. Proteoglycan 4 expression protects against the development of osteoarthritis. Sci. Transl. Med. 5, 176ra34 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Flannery, C. R. et al. Prevention of cartilage degeneration in a rat model of osteoarthritis by intraarticular treatment with recombinant lubricin. Arthritis Rheum. 60, 840–847 (2009).

    Article  CAS  PubMed  Google Scholar 

  134. Jay, G. D. et al. Prevention of cartilage degeneration and restoration of chondroprotection by lubricin tribosupplementation in the rat following anterior cruciate ligament transection. Arthritis Rheum. 62, 2382–2391 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Hosaka, Y. et al. Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development. Proc. Natl Acad. Sci. USA 110, 1875–1880 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Kamekura, S. et al. Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. Arthritis Rheum. 54, 2462–2470 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. Kadri, A. et al. Inhibition of bone resorption blunts osteoarthritis in mice with high bone remodelling. Ann. Rheum. Dis. 69, 1533–1538 (2010).

    Article  PubMed  Google Scholar 

  138. Echtermeyer, F. et al. Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis. Nat. Med. 15, 1072–1076 (2009).

    Article  CAS  PubMed  Google Scholar 

  139. Lin, A. C. et al. Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat. Med. 15, 1421–1425 (2009).

    Article  CAS  PubMed  Google Scholar 

  140. Orlandi, A. et al. Transglutaminase-2 differently regulates cartilage destruction and osteophyte formation in a surgical model of osteoarthritis. Amino Acids 36, 755–763 (2009).

    Article  CAS  PubMed  Google Scholar 

  141. Little, C. B. et al. Matrix metalloproteinases are not essential for aggrecan turnover during normal skeletal growth and development. Mol. Cell. Biol. 25, 3388–3399 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Clements, K. M. et al. Gene deletion of either interleukin-1β, interleukin-1β-converting enzyme, inducible nitric oxide synthase, or stromelysin 1 accelerates the development of knee osteoarthritis in mice after surgical transection of the medial collateral ligament and partial medial meniscectomy. Arthritis Rheum. 48, 3452–3463 (2003).

    Article  CAS  PubMed  Google Scholar 

  143. Rudolphi, K., Gerwin, N., Verzijl, N., van der Kraan, P. & van den Berg, W. Pralnacasan, an inhibitor of interleukin-1β converting enzyme, reduces joint damage in two murine models of osteoarthritis. Osteoarthritis Cartilage 11, 738–746 (2003).

    Article  CAS  PubMed  Google Scholar 

  144. Jeon, J. et al. Cytokine-like 1 knock-out mice (Cytl1−/−) show normal cartilage and bone development but exhibit augmented osteoarthritic cartilage destruction. J. Biol. Chem. 286, 27206–27213 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Chia, S. L. et al. Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS-5 and delays cartilage degradation in murine osteoarthritis. Arthritis Rheum. 60, 2019–2027 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Inoue, A. et al. The therapeutic effects of basic fibroblast growth factor contained in gelatin hydrogel microspheres on experimental osteoarthritis in the rabbit knee. Arthritis Rheum. 54, 264–270 (2006).

    Article  CAS  PubMed  Google Scholar 

  147. Lodewyckx, L., Luyten, F. P. & Lories, R. J. Genetic deletion of low-density lipoprotein receptor-related protein 5 increases cartilage degradation in instability-induced osteoarthritis. Rheumatology (Oxford) 51, 1973–1978 (2012).

    Article  CAS  Google Scholar 

  148. Miyaki, S. et al. MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev. 24, 1173–1185 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Pelletier, J. P. et al. Reduced progression of experimental osteoarthritis in vivo by selective inhibition of inducible nitric oxide synthase. Arthritis Rheum. 41, 1275–1286 (1998).

    Article  CAS  PubMed  Google Scholar 

  150. Pelletier, J. P. et al. Selective inhibition of inducible nitric oxide synthase in experimental osteoarthritis is associated with reduction in tissue levels of catabolic factors. J. Rheumatol. 26, 2002–2014 (1999).

    CAS  PubMed  Google Scholar 

  151. Matsui, Y. et al. Accelerated development of aging-associated and instability-induced osteoarthritis in osteopontin-deficient mice. Arthritis Rheum. 60, 2362–2371 (2009).

    Article  CAS  PubMed  Google Scholar 

  152. Otsuki, S. et al. Extracellular sulfatases support cartilage homeostasis by regulating BMP and FGF signaling pathways. Proc. Natl Acad. Sci. USA 107, 10202–10207 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Okamura, N. et al. Deficiency of tenascin-C delays articular cartilage repair in mice. Osteoarthritis Cartilage 18, 839–848 (2009).

    Article  PubMed  Google Scholar 

  154. Mi, M. et al. TIMP2 deficient mice develop accelerated osteoarthritis via promotion of angiogenesis upon destabilization of the medial meniscus. Biochem. Biophys. Res. Commun. 423, 366–372 (2012).

    Article  CAS  PubMed  Google Scholar 

  155. Shimizu, S. et al. Prevention of cartilage destruction with intraarticular osteoclastogenesis inhibitory factor/osteoprotegerin in a murine model of osteoarthritis. Arthritis Rheum. 56, 3358–3365 (2007).

    Article  PubMed  Google Scholar 

  156. Seito, N. et al. Interruption of glycosphingolipid synthesis enhances osteoarthritis development in mice. Arthritis Rheum. 64, 2579–2588 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Chen, L. et al. IL-17RA aptamer-mediated repression of IL-6 inhibits synovium inflammation in a murine model of osteoarthritis. Osteoarthritis Cartilage 19, 711–718 (2011).

    Article  CAS  PubMed  Google Scholar 

  158. Burleigh, A. et al. Joint immobilization prevents murine osteoarthritis and reveals the highly mechanosensitive nature of protease expression in vivo. Arthritis Rheum. 64, 2278–2288 (2012).

    Article  CAS  PubMed  Google Scholar 

  159. Diekman, B. O. et al. Intra-articular delivery of purified mesenchymal stem cells from C57BL/6 or MRL/MpJ superhealer mice prevents post-traumatic arthritis. Cell Transplant http://dx.doi.org/10.3727/096368912X653264.

  160. Carames, B. et al. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann. Rheum. Dis. 71, 575–581 (2012).

    Article  CAS  PubMed  Google Scholar 

  161. Song, J. et al. MicroRNA-181b regulates articular chondrocytes differentiation and cartilage integrity. Biochem. Biophys. Res. Commun. 431, 210–214 (2013).

    Article  CAS  PubMed  Google Scholar 

  162. McNamee, K. E. et al. Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role for nerve growth factor in non-inflammatory joint pain. Pain 149, 386–392 (2010).

    Article  CAS  PubMed  Google Scholar 

  163. Kadri, A. et al. Inhibition of bone resorption blunts osteoarthritis in mice with high bone remodelling. Ann. Rheum. Dis. 69, 1533–1538 (2010).

    Article  PubMed  Google Scholar 

  164. Sampson, E. R. et al. Teriparatide as a chondroregenerative therapy for injury-induced osteoarthritis. Sci. Transl. Med. 3, 101ra93 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Aini, H. et al. Procyanidin B3 prevents articular cartilage degeneration and heterotopic cartilage formation in a mouse surgical osteoarthritis model. PLoS ONE 7, e37728 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Yano, F. et al. A novel disease-modifying osteoarthritis drug candidate targeting Runx1. Ann. Rheum. Dis. 72, 748–753 (2013).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge generous funding support for direct research costs and salaries for research personnel, received in grants from the National Institutes of Health, National Health and Medical Research Council of Australia, the Australian Research Council, Arthritis Australia, and the University of Sydney.

Author information

Authors and Affiliations

  1. Raymond Purves Bone and Joint Research Laboratories, Kolling Institute of Medical Research, Institute of Bone and Joint Research, University of Sydney at Royal North Shore Hospital, St Leonards, 2065, NSW, Australia

    Christopher B. Little

  2. Department of Rheumatology, Kolling Institute of Medical Research, Institute of Bone and Joint Research, University of Sydney at Royal North Shore Hospital, St Leonards, 2065, NSW, Australia

    David J. Hunter

Authors
  1. Christopher B. Little
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David J. Hunter
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors contributed equally to researching data, reviewing the literature, discussing content, writing and revising the article.

Corresponding author

Correspondence to Christopher B. Little.

Ethics declarations

Competing interests

C. Little declares that he has received honoraria from AMGEN, Fidia Farmaceutici, and Pfizer, and has received research support from Fidia Farmaceutici, Eli Lilly and Pfizer. D. Hunter declares that he holds or has applied for a patent with DonJoy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Little, C., Hunter, D. Post-traumatic osteoarthritis: from mouse models to clinical trials. Nat Rev Rheumatol 9, 485–497 (2013). https://doi.org/10.1038/nrrheum.2013.72

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2013.72

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing