Skip to main content

Advertisement

SpringerLink
Log in

Novel Insights into Osteoarthritis Joint Pathology from Studies in Mice

  • Osteoarthritis (MB Goldring, Section Editor)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Osteoarthritis causes tremendous individual suffering and staggering societal costs, but due to our limited understanding of the underlying molecular and cellular mechanisms, our avenues for treating this disease are very restricted. Recent years have seen a drastic increase in the use of genetically modified mice to characterize the pathophysiology of osteoarthritis. Many new players and mechanisms driving osteoarthritis pathogenesis have been elucidated, some of which might be strong candidates as therapeutic targets for the human disease. The current review summarizes key findings (selected subjectively by the authors) from mouse osteoarthritis studies over recent years.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, et al. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014;73(7):1323–30. doi:10.1136/annrheumdis-2013-204763.

    Article  PubMed  Google Scholar 

  2. Hunter DJ, Schofield D, Callander E. The individual and socioeconomic impact of osteoarthritis. Nat Rev Rheumatol. 2014;10(7):437–41. doi:10.1038/nrrheum.2014.44.

    PubMed  Google Scholar 

  3. Bijlsma JWJ, Berenbaum F, Lafeber FPJG. Osteoarthritis: an update with relevance for clinical practice. Lancet. 2011;377(9783):2115–26. doi:10.1016/s0140-6736(11)60243-2.

    Article  PubMed  Google Scholar 

  4. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58(1):26–35. doi:10.1002/art.23176.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Chu CR, Williams AA, Coyle CH, Bowers ME. Early diagnosis to enable early treatment of pre-osteoarthritis. Arthritis Res Ther. 2012;14(3):212. doi:10.1186/ar3845.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Fang H, Beier F. Mouse models of osteoarthritis: modelling risk factors and assessing outcomes. Nat Rev Rheumatol. 2014;10(7):413–21. doi:10.1038/nrrheum.2014.46.

    Article  PubMed  Google Scholar 

  7. Aigner T, Sachse A, Gebhard PM, Roach HI. Osteoarthritis: pathobiology-targets and ways for therapeutic intervention. Adv Drug Deliv Rev. 2006;58(2):128–49. doi:10.1016/j.addr.2006.01.020.

    Article  CAS  PubMed  Google Scholar 

  8. Sandell LJ, Aigner T. Articular cartilage and changes in arthritis. An introduction: cell biology of osteoarthritis. Arthritis Res. 2001;3(2):107–13.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Stanton H, Rogerson FM, East CJ, Golub SB, Lawlor KE, Meeker CT, et al. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature. 2005;434(7033):648–52. doi:10.1038/nature03417.

    Article  CAS  PubMed  Google Scholar 

  10. Malfait AM, Liu RQ, Ijiri K, Komiya S, Tortorella MD. Inhibition of ADAM-TS4 and ADAM-TS5 prevents aggrecan degradation in osteoarthritic cartilage. J Biol Chem. 2002;277(25):22201–8. doi:10.1074/jbc.M200431200.

    Article  CAS  PubMed  Google Scholar 

  11. Troeberg L, Nagase H. Proteases involved in cartilage matrix degradation in osteoarthritis. Biochim Biophys Acta. 2012;1824(1):133–45. doi:10.1016/j.bbapap.2011.06.020.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Wang M, Sampson ER, Jin H, Li J, Ke QH, Im HJ, et al. MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res Ther. 2013;15(1):R5. doi:10.1186/ar4133.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Billinghurst RC, Dahlberg L, Ionescu M, Reiner A, Bourne R, Rorabeck C, et al. Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage. J Clin Investig. 1997;99(7):1534–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Caterson B, Flannery CR, Hughes CE, Little CB. Mechanisms involved in cartilage proteoglycan catabolism. Matrix Biol. 2000;19(4):333–44. doi:10.1016/S0945-053X(00)00078-0.

    Article  CAS  PubMed  Google Scholar 

  15. Fosang AJ, Little CB. Drug insight: aggrecanases as therapeutic targets for osteoarthritis. Nat Clin Pract Rheumatol. 2008;4(8):420–7.

    Article  CAS  PubMed  Google Scholar 

  16. Karsdal MA, Madsen SH, Christiansen C, Henriksen K, Fosang AJ, Sondergaard BC. Cartilage degradation is fully reversible in the presence of aggrecanase but not matrix metalloproteinase activity. Arthritis Res Ther. 2008;10(3):R63. doi:10.1186/ar2434.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Little CB, Fosang AJ. Is cartilage matrix breakdown an appropriate therapeutic target in osteoarthritis—insights from studies of aggrecan and collagen proteolysis? Curr Drug Targets. 2010;11(5):561–75.

    Article  CAS  PubMed  Google Scholar 

  18. Li NG, Shi ZH, Tang YP, Wang ZJ, Song SL, Qian LH, et al. New hope for the treatment of osteoarthritis through selective inhibition of MMP-13. Curr Med Chem. 2011;18(7):977–1001.

    Article  CAS  PubMed  Google Scholar 

  19. Schipani E. Hypoxia and HIF-1α in chondrogenesis. Semin Cell Dev Biol. 2005;16(4–5):539–46. doi:10.1016/j.semcdb.2005.03.003.

    Article  CAS  PubMed  Google Scholar 

  20. Ryu JH, Yang S, Shin Y, Rhee J, Chun CH, Chun JS. Interleukin-6 plays an essential role in hypoxia-inducible factor 2alpha-induced experimental osteoarthritic cartilage destruction in mice. Arthritis Rheum. 2011;63(9):2732–43. doi:10.1002/art.30451.

    Article  CAS  PubMed  Google Scholar 

  21. Yang S, Kim J, Ryu JH, Oh H, Chun CH, Kim BJ, et al. Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction. Nat Med. 2010;16(6):687–93. doi:10.1038/nm.2153.

    Article  CAS  PubMed  Google Scholar 

  22. Saito T, Fukai A, Mabuchi A, Ikeda T, Yano F, Ohba S, et al. Transcriptional regulation of endochondral ossification by HIF-2[alpha] during skeletal growth and osteoarthritis development. Nat Med. 2010;16(6):678–86. http://www.nature.com/nm/journal/v16/n6/suppinfo/nm.2146_S1.html.

    Article  CAS  PubMed  Google Scholar 

  23. Caramés B, Taniguchi N, Otsuki S, Blanco FJ, Lotz M. Autophagy is a protective mechanism in normal cartilage and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum. 2010;62(3):791–801. doi:10.1002/art.27305.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Mizushima N. Physiological functions of autophagy. Curr Top Microbiol Immunol. 2009;335:71–84. doi:10.1007/978-3-642-00302-8_3.

    CAS  PubMed  Google Scholar 

  25. Zhang Y, Vasheghani F, Li YH, Blati M, Simeone K, Fahmi H, et al. Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis. Ann Rheum Dis. 2014. doi:10.1136/annrheumdis-2013-204599.

    Google Scholar 

  26. Carames B, Hasegawa A, Taniguchi N, Miyaki S, Blanco FJ, Lotz M. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann Rheum Dis. 2012;71(4):575–81. doi:10.1136/annrheumdis-2011-200557.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell. 2009;20(7):1981–91. doi:10.1091/mbc.E08-12-1248.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Weng T, Xie Y, Yi L, Huang J, Luo F, Du X, et al. Loss of Vhl in cartilage accelerated the progression of age-associated and surgically induced murine osteoarthritis. Osteoarthr Cartil. 2014;22(8):1197–205. doi:10.1016/j.joca.2014.06.031.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Huang MJ, Wang L, Jin DD, Zhang ZM, Chen TY, Jia CH, et al. Enhancement of the synthesis of n-3 PUFAs in fat-1 transgenic mice inhibits mTORC1 signalling and delays surgically induced osteoarthritis in comparison with wild-type mice. Ann Rheum Dis. 2014;73(9):1719–27. doi:10.1136/annrheumdis-2013-203231.

    Article  CAS  PubMed  Google Scholar 

  30. Dreyer C, Keller H, Mahfoudi A, Laudet V, Krey G, Wahli W. Positive regulation of the peroxisomal beta-oxidation pathway by fatty acids through activation of peroxisome proliferator-activated receptors (PPAR). Biol Cell. 1993;77(1):67–76.

    Article  CAS  PubMed  Google Scholar 

  31. Naruhn S, Meissner W, Adhikary T, Kaddatz K, Klein T, Watzer B, et al. 15-Hydroxyeicosatetraenoic acid is a preferential peroxisome proliferator-activated receptor beta/delta agonist. Mol Pharmacol. 2010;77(2):171–84. doi:10.1124/mol.109.060541.

    Article  CAS  PubMed  Google Scholar 

  32. Kapadia R, Yi J-H, Vemuganti R. Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. Front Biosci. 2008;13:1813–26.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Monemdjou R, Vasheghani F, Fahmi H, Perez G, Blati M, Taniguchi N, et al. Association of cartilage-specific deletion of peroxisome proliferator-activated receptor gamma with abnormal endochondral ossification and impaired cartilage growth and development in a murine model. Arthritis Rheum. 2012;64(5):1551–61. doi:10.1002/art.33490.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Vasheghani F, Monemdjou R, Fahmi H, Zhang Y, Perez G, Blati M, et al. Adult cartilage-specific peroxisome proliferator-activated receptor gamma knockout mice exhibit the spontaneous osteoarthritis phenotype. Am J Pathol. 2013;182(4):1099–106. doi:10.1016/j.ajpath.2012.12.012.

    Article  CAS  PubMed  Google Scholar 

  35. Vasheghani F, Zhang Y, Li YH, Blati M, Fahmi H, Lussier B, et al. PPARgamma deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage. Ann Rheum Dis. 2015;74(3):569–78. doi:10.1136/annrheumdis-2014-205743. In this very recent study by Vasheghani et al. a critical link between metabolic dysregulation and disrupted autophagy mediated by enhanced mTOR signalling is proposed. As we attempt to put together a more complete picture of joint pathology in OA, studies linking critical mediators of various important homeostatic and catabolic process are of tremendous value.

    Article  PubMed Central  PubMed  Google Scholar 

  36. Ratneswaran A, LeBlanc EA, Walser E, Welch I, Mort JS, Borradaile N, et al. Peroxisome proliferator-activated receptor delta promotes the progression of posttraumatic osteoarthritis in a mouse model. Arthritis Rheumatol (Hoboken, NJ). 2015;67(2):454–64. doi:10.1002/art.38915.

    Article  CAS  Google Scholar 

  37. Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Mänttäri M, Heinonen OP, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment. Circulation. 1992;85(1):37–45.

    Article  CAS  PubMed  Google Scholar 

  38. de Munter W, Blom AB, Helsen MM, Walgreen B, van der Kraan PM, Joosten LA, et al. Cholesterol accumulation caused by low density lipoprotein receptor deficiency or a cholesterol-rich diet results in ectopic bone formation during experimental osteoarthritis. Arthritis Res Ther. 2013;15(6):R178. doi:10.1186/ar4367.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Triantaphyllidou IE, Kalyvioti E, Karavia E, Lilis I, Kypreos KE, Papachristou DJ. Perturbations in the HDL metabolic pathway predispose to the development of osteoarthritis in mice following long-term exposure to western-type diet. Osteoarthr Cartil. 2013;21(2):322–30. doi:10.1016/j.joca.2012.11.003.

    Article  PubMed  Google Scholar 

  40. Gierman LM, Kuhnast S, Koudijs A, Pieterman EJ, Kloppenburg M, van Osch GJ, et al. Osteoarthritis development is induced by increased dietary cholesterol and can be inhibited by atorvastatin in APOE*3Leiden.CETP mice—a translational model for atherosclerosis. Ann Rheum Dis. 2014;73(5):921–7. doi:10.1136/annrheumdis-2013-203248.

    Article  CAS  PubMed  Google Scholar 

  41. Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov. 2005;4(12):977–87.

    Article  CAS  PubMed  Google Scholar 

  42. Bush JR, Berube NG, Beier F. A new prescription for growth? Statins, cholesterol and cartilage homeostasis. Osteoarthr Cartil. 2015;23(4):503–6. doi:10.1016/j.joca.2015.01.002.

    Article  CAS  PubMed  Google Scholar 

  43. Goldring MB, Otero M, Plumb DA, Dragomir C, Favero M, El Hachem K, et al. Roles of inflammatory and anabolic cytokines in cartilage metabolism: signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis. Eur Cells Mater. 2011;21:202–20.

    CAS  Google Scholar 

  44. Gierman LM, van der Ham F, Koudijs A, Wielinga PY, Kleemann R, Kooistra T, et al. Metabolic stress-induced inflammation plays a major role in the development of osteoarthritis in mice. Arthritis Rheum. 2012;64(4):1172–81. doi:10.1002/art.33443.

    Article  CAS  PubMed  Google Scholar 

  45. Mold C, Gewurz H, Du Clos TW. Regulation of complement activation by C-reactive protein. Immunopharmacology. 1999;42(1–3):23–30. doi:10.1016/S0162-3109(99)00007-7.

    Article  CAS  PubMed  Google Scholar 

  46. Wang Q, Rozelle AL, Lepus CM, Scanzello CR, Song JJ, Larsen DM, et al. Identification of a central role for complement in osteoarthritis. Nat Med. 2011;17(12):1674–9. doi:10.1038/nm.2543.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Takebe K, Rai MF, Schmidt EJ, Sandell LJ. The chemokine receptor CCR5 plays a role in post-traumatic cartilage loss in mice, but does not affect synovium and bone. Osteoarthr Cartil. 2015;23(3):454–61. doi:10.1016/j.joca.2014.12.002.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Thomas N, Li P, Fleming BC, Chen Q, Wei X, Pan X, et al. Attenuation of cartilage pathogenesis in post-traumatic osteoarthritis (PTOA) in mice by blocking the stromal derived factor 1 receptor (CXCR4) with the specific inhibitor, AMD3100. J Orthop Res. 2015. doi:10.1002/jor.22862.

    PubMed  Google Scholar 

  49. Sherwood J, Bertrand J, Nalesso G, Poulet B, Pitsillides A, Brandolini L, et al. A homeostatic function of CXCR2 signalling in articular cartilage. Ann Rheum Dis. 2014. doi:10.1136/annrheumdis-2014-205546. This novel paper by Sherwood et al. presents exciting new insights into the homeostatic regulation of articular cartilage by an unlikely factor, CXCR2. This is of importance to the field because generally chemokine signaling is viewed as catabolic, but in this case the opposite appears to be true.

    PubMed  Google Scholar 

  50. Kozhemyakina E, Lassar AB, Zelzer E. A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation. Development (Cambridge, England). 2015;142(5):817–31. doi:10.1242/dev.105536.

    Article  CAS  Google Scholar 

  51. Pitsillides AA, Beier F. Cartilage biology in osteoarthritis—lessons from developmental biology. Nat Rev Rheumatol. 2011;7(11):654–63. doi:10.1038/nrrheum.2011.129.

    Article  CAS  PubMed  Google Scholar 

  52. Sun MM-G, Beier F. Chondrocyte hypertrophy in skeletal development, growth, and disease. Birth Defects Res C Embryo Today Rev. 2014;102(1):74–82. doi:10.1002/bdrc.21062.

    Article  CAS  Google Scholar 

  53. Luyten FP, Tylzanowski P, Lories RJ. Wnt signaling and osteoarthritis. Bone. 2009;44(4):522–7. doi:10.1016/j.bone.2008.12.006.

    Article  CAS  PubMed  Google Scholar 

  54. Zhu M, Tang D, Wu Q, Hao S, Chen M, Xie C, et al. Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice. J Bone Min Res Off J Am Soc Bone Miner Res. 2009;24(1):12–21. doi:10.1359/jbmr.080901.

    Article  CAS  Google Scholar 

  55. Yuasa T, Otani T, Koike T, Iwamoto M, Enomoto-Iwamoto M. Wnt/beta-catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes: its possible role in joint degeneration. Lab Investig. 2008;88(3):264–74. doi:10.1038/labinvest.3700747.

    Article  CAS  PubMed  Google Scholar 

  56. Litherland GJ, Hui W, Elias MS, Wilkinson DJ, Watson S, Huesa C, et al. Glycogen synthase kinase 3 inhibition stimulates human cartilage destruction and exacerbates murine osteoarthritis. Arthritis Rheumatol (Hoboken, NJ). 2014;66(8):2175–87. doi:10.1002/art.38681.

    Article  CAS  Google Scholar 

  57. Funck-Brentano T, Bouaziz W, Marty C, Geoffroy V, Hay E, Cohen-Solal M. Dkk-1-mediated inhibition of Wnt signaling in bone ameliorates osteoarthritis in mice. Arthritis Rheumatol (Hoboken, NJ). 2014;66(11):3028–39. doi:10.1002/art.38799.

    Article  CAS  Google Scholar 

  58. Oh H, Chun CH, Chun JS. Dkk-1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice. Arthritis Rheum. 2012;64(8):2568–78. doi:10.1002/art.34481.

    Article  CAS  PubMed  Google Scholar 

  59. Zhu M, Chen M, Zuscik M, Wu Q, Wang Y-J, Rosier RN, et al. Inhibition of β-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum. 2008;58(7):2053–64. doi:10.1002/art.23614.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Tamamura Y, Otani T, Kanatani N, Koyama E, Kitagaki J, Komori T, et al. Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification. J Biol Chem. 2005;280(19):19185–95. doi:10.1074/jbc.M414275200.

    Article  CAS  PubMed  Google Scholar 

  61. Chen CG, Thuillier D, Chin EN, Alliston T. Chondrocyte-intrinsic Smad3 represses Runx2-inducible matrix metalloproteinase 13 expression to maintain articular cartilage and prevent osteoarthritis. Arthritis Rheum. 2012;64(10):3278–89. doi:10.1002/art.34566.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Davidson ENB, Van der Kraan PM, van Den Berg WB. TGF-β and osteoarthritis. Osteoarthr Cartil. 2007;15(6):597–604.

    Article  Google Scholar 

  63. Meulenbelt I, Bos SD, Chapman K, van der Breggen R, Houwing-Duistermaat JJ, Kremer D, et al. Meta-analyses of genes modulating intracellular T3 bio-availability reveal a possible role for the DIO3 gene in osteoarthritis susceptibility. Ann Rheum Dis. 2011;70(1):164–7.

    Article  PubMed  Google Scholar 

  64. Bomer N, Cornelis FM, Ramos YF, den Hollander W, Storms L, van der Breggen R, et al. The effect of forced exercise on knee joints in Dio2−/− mice: type II iodothyronine deiodinase-deficient mice are less prone to develop OA-like cartilage damage upon excessive mechanical stress. Ann Rheum Dis. 2014. doi:10.1136/annrheumdis-2014-206608. Our highlighting of this study by Bomer et al. is based on 2 factors. Firstly, this study identifies Dio2, a gene linked to increased OA susceptibility in humans, as a novel mediator of joint pathology in OA in mice. Secondly, it presents an exciting new mouse model of OA induction for the community that ultimately provides a more physiological model of disease induction and progression.

    Google Scholar 

  65. Waung JA, Bassett JH, Williams GR. Adult mice lacking the type 2 iodothyronine deiodinase have increased subchondral bone but normal articular cartilage. Thyroid Off J Am Thyroid Assoc. 2015;25(3):269–77. doi:10.1089/thy.2014.0476.

    Article  CAS  Google Scholar 

  66. Zhang X, Zhu J, Li Y, Lin T, Siclari VA, Chandra A, et al. Epidermal growth factor receptor (EGFR) signaling regulates epiphyseal cartilage development through β-catenin-dependent and -independent pathways. J Biol Chem. 2013;288(45):32229–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Zhang X, Siclari VA, Lan S, Zhu J, Koyama E, Dupuis HL, et al. The critical role of the epidermal growth factor receptor in endochondral ossification. J Bone Miner Res. 2011;26(11):2622–33. doi:10.1002/jbmr.502.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Appleton CTG, Usmani SE, Bernier SM, Aigner T, Beier F. Transforming growth factor α suppression of articular chondrocyte phenotype and Sox9 expression in a rat model of osteoarthritis. Arthritis Rheum. 2007;56(11):3693–705. doi:10.1002/art.22968.

    Article  PubMed  Google Scholar 

  69. Appleton CTG, Usmani SE, Mort JS, Beier F. Rho/ROCK and MEK/ERK activation by transforming growth factor-[alpha] induces articular cartilage degradation. Lab Investig. 2009;90(1):20–30.

    Article  PubMed  Google Scholar 

  70. Zhang Y-W, Su Y, Lanning N, Swiatek PJ, Bronson RT, Sigler R, et al. Targeted disruption of Mig-6 in the mouse genome leads to early onset degenerative joint disease. Proc Natl Acad Sci U S A. 2005;102(33):11740–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Staal B, Williams BO, Beier F, Vande Woude GF, Zhang YW. Cartilage-specific deletion of Mig-6 results in osteoarthritis-like disorder with excessive articular chondrocyte proliferation. Proc Natl Acad Sci U S A. 2014;111(7):2590–5. doi:10.1073/pnas.1400744111.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Pest MA, Russell BA, Zhang YW, Jeong JW, Beier F. Disturbed cartilage and joint homeostasis resulting from a loss of mitogen-inducible gene 6 in a mouse model of joint dysfunction. Arthritis Rheumatol (Hoboken, NJ). 2014;66(10):2816–27. doi:10.1002/art.38758.

    Article  CAS  Google Scholar 

  73. Shepard JB, Jeong JW, Maihle NJ, O’Brien S, Dealy CN. Transient anabolic effects accompany epidermal growth factor receptor signal activation in articular cartilage in vivo. Arthritis Res Ther. 2013;15(3):R60. doi:10.1186/ar4233.

    Article  PubMed Central  PubMed  Google Scholar 

  74. Joiner DM, Less KD, Van Wieren EM, Zhang YW, Hess D, Williams BO. Accelerated and increased joint damage in young mice with global inactivation of mitogen-inducible gene 6 after ligament and meniscus injury. Arthritis Res Ther. 2014;16(2):R81. doi:10.1186/ar4522.

    Article  PubMed Central  PubMed  Google Scholar 

  75. Lories RJ, Luyten FP. The bone-cartilage unit in osteoarthritis. Nat Rev Rheumatol. 2011;7(1):43–9. doi:10.1038/nrrheum.2010.197.

    Article  CAS  PubMed  Google Scholar 

  76. Roman-Blas JA, Herrero-Beaumont G. Targeting subchondral bone in osteoporotic osteoarthritis. Arthritis Res Ther. 2014;16(6):494. doi:10.1186/s13075-014-0494-0.

    Article  PubMed Central  PubMed  Google Scholar 

  77. Funck-Brentano T, Lin H, Hay E, Ah Kioon MD, Schiltz C, Hannouche D, et al. Targeting bone alleviates osteoarthritis in osteopenic mice and modulates cartilage catabolism. PLoS One. 2012;7(3), e33543. doi:10.1371/journal.pone.0033543.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Zhen G, Wen C, Jia X, Li Y, Crane JL, Mears SC, et al. Inhibition of TGF-[beta] signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med. 2013;19(6):704–12. doi:10.1038/nm.3143. http://www.nature.com/nm/journal/v19/n6/abs/nm.3143.html-supplementary-information.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Bush JR, Beier F. TGF-[beta] and osteoarthritis—the good and the bad. Nat Med. 2013;19(6):667–9. doi:10.1038/nm.3228.

    Article  CAS  PubMed  Google Scholar 

  80. Jackson MT, Moradi B, Zaki S, Smith MM, McCracken S, Smith SM, et al. Depletion of protease-activated receptor 2 but not protease-activated receptor 1 may confer protection against osteoarthritis in mice through extracartilaginous mechanisms. Arthritis Rheumatol (Hoboken, NJ). 2014;66(12):3337–48. doi:10.1002/art.38876.

    Article  CAS  Google Scholar 

  81. van der Kraan PM, van den Berg WB. Osteophytes: relevance and biology. Osteoarthr Cartil. 2007;15(3):237–44. doi:10.1016/j.joca.2006.11.006.

    Article  PubMed  Google Scholar 

  82. Menkes CJ, Lane NE. Are osteophytes good or bad? Osteoarthr Cartil. 2004;12(Suppl A):S53–4.

    Article  PubMed  Google Scholar 

  83. Kaneko H, Ishijima M, Futami I, Tomikawa-Ichikawa N, Kosaki K, Sadatsuki R, et al. Synovial perlecan is required for osteophyte formation in knee osteoarthritis. Matrix Biol. 2013;32(3–4):178–87. doi:10.1016/j.matbio.2013.01.004.

    Article  CAS  PubMed  Google Scholar 

  84. Davidson EN, Vitters EL, Bennink MB, van Lent PL, van Caam AP, Blom AB, et al. Inducible chondrocyte-specific overexpression of BMP2 in young mice results in severe aggravation of osteophyte formation in experimental OA without altering cartilage damage. Ann Rheum Dis. 2014. doi:10.1136/annrheumdis-2013-204528.

    PubMed  Google Scholar 

  85. Chen L, Li DQ, Zhong J, Wu XL, Chen Q, Peng H, et al. IL-17RA aptamer-mediated repression of IL-6 inhibits synovium inflammation in a murine model of osteoarthritis. Osteoarthr Cartil. 2011;19(6):711–8. doi:10.1016/j.joca.2011.01.018.

    Article  CAS  PubMed  Google Scholar 

  86. Zanotti S, Canalis E. Interleukin 6 mediates selected effects of Notch in chondrocytes. Osteoarthr Cartil. 2013;21(11):1766–73. doi:10.1016/j.joca.2013.08.010.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Fosang AJ, Lees S, Golub SB, Last K, Zeng W, Jackson DC, et al. Bioactivity in an aggrecan 32mer fragment is mediated via Toll-like receptor 2. Arthritis Rheumatol. 2015. doi:10.1002/art.39063.

    PubMed  Google Scholar 

  88. Bondeson J, Wainwright SD, Lauder S, Amos N, Hughes CE. The role of synovial macrophages and macrophage-produced cytokines in driving aggrecanases, matrix metalloproteinases, and other destructive and inflammatory responses in osteoarthritis. Arthritis Res Ther. 2006;8(6):R187. doi:10.1186/ar2099.

    Article  PubMed Central  PubMed  Google Scholar 

  89. Miller RE, Tran PB, Das R, Ghoreishi-Haack N, Ren D, Miller RJ, et al. CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis. Proc Natl Acad Sci U S A. 2012;109(50):20602–7. doi:10.1073/pnas.1209294110.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Cuellar JM, Scuderi GJ, Cuellar VG, Golish SR, Yeomans DC. Diagnostic utility of cytokine biomarkers in the evaluation of acute knee pain. J Bone Joint Surg Am. 2009;91(10):2313–20. doi:10.2106/jbjs.h.00835.

    Article  PubMed  Google Scholar 

  91. Pest MA, Beier F. Developmental biology: is there such a thing as a cartilage-specific knockout mouse? Nat Rev Rheumatol. 2014;10(12):702–4. doi:10.1038/nrrheum.2014.168.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We apologize to our colleagues whose relevant studies could not be incorporated here because of space restrictions. We acknowledge support for P.M. from a Canadian Institutes of Health Research (CIHR) MD/PhD scholarship and for F.B. from a Canada Research Chair Award. Research in the lab of F.B. is supported by operating grants from CIHR.

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Paxton M. Moon and Frank Beier declare no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by the authors.

Author information

Authors and Affiliations

  1. Department of Physiology and Pharmacology, Western University, London, Ontario, Canada

    Paxton M. Moon & Frank Beier

  2. Children’s Health Research Institute, London, Ontario, Canada

    Frank Beier

Authors
  1. Paxton M. Moon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frank Beier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frank Beier.

Additional information

This article is part of the Topical Collection on Osteoarthritis

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moon, P.M., Beier, F. Novel Insights into Osteoarthritis Joint Pathology from Studies in Mice. Curr Rheumatol Rep 17, 50 (2015). https://doi.org/10.1007/s11926-015-0524-1

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11926-015-0524-1

Keywords

Search

Navigation