Mouse Genetics pp 401-419 | Cite as

Experimental Osteoarthritis Models in Mice

  • Julia Lorenz
  • Susanne Grässel
Part of the Methods in Molecular Biology book series (MIMB, volume 1194)


Osteoarthritis (OA) is a slowly progressing, degenerative disorder of synovial joints culminating in the irreversible destruction of articular cartilage and subchondral bone. It affects almost everyone over the age of 65 and influences life quality of affected individuals with enormous costs to the health care system. Current therapeutic strategies seek to ameliorate pain and increase mobility; however, to date none of them halts disease progression or regenerates damaged cartilage or bone. Thus, there is an ultimate need for the development of new, noninvasive treatments that could substitute joint replacement for late- or end-stage patients. Therefore, osteoarthritis animal models for mimicking of all OA features are important. Mice develop an OA pathology that is comparable to humans, rapidly develop OA due to the short lifetime and show reproducible OA symptoms. They provide a versatile and widely used animal model for analyzing molecular mechanisms of OA pathology. One major advantage over large animal models is the availability of knockout or transgenic mice strains to examine genetic predispositions/contributions to OA.

In this chapter, we describe three widely used instability-inducing murine osteoarthritis models. The most common two methods for surgical induction are: (1) destabilization of the medial meniscus (DMM) and (2) anterior cruciate ligament transection (ACLT). In the DMM model, the medial meniscotibial ligament is transected while in the ACLT model the anterior cruciate ligament is destroyed. In the third, chemical induced instability method, intraarticular collagenase is injected into the knee joint. Intraarticular collagenase weakens articular ligaments which cause instability of the joint, and full-blown OA develops within 6 weeks. For morphological evaluation, we correspond mainly to the recommendations of OARSI for histological assessment of osteoarthritis in mouse. For statistical evaluation summed or mean scores of all four knee areas (medial tibial plateau (MTP), medial tibial condyle (MFC), lateral tibial plateau (LTP) or lateral femoral condyle (LFC)), medial and/or lateral regions are used.

In future, not only large animal models like guinea pigs, sheep, goats, or horses will be important for a better understanding of osteoarthritis, but especially the mouse model with its rapid development of osteoarthritis and its numerous advantages by providing knockout or transgenic strains will become more and more relevant for drug development and determination of genetic predispositions of osteoarthritis pathology.

Key words

Osteoarthritis Articular cartilage Mouse model Destabilization of medial meniscus (DMM) Anterior cruciate ligament transection (ACLT) Intraarticular collagenase injection 



This work was supported by the DFG grant GR1301/9-1 assigned to SG.


  1. 1.
    Pitsillides AA, Beier F (2011) Cartilage biology in osteoarthritis-lessons from developmental biology. Nat Rev Rheumatol 7(11):654–663PubMedCrossRefGoogle Scholar
  2. 2.
    van den Berg WB (2011) Osteoarthritis year 2010 in review: pathomechanisms. Osteoarthritis Cartilage 19(4):338–341PubMedCrossRefGoogle Scholar
  3. 3.
    Dreier R (2010) Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders. Arthritis Res Ther 12(5):216PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Goldring MB, Marcu KB (2009) Cartilage homeostasis in health and rheumatic diseases. Arthritis Res Ther 11(3):224PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Alsalameh S, Amin R, Gemba T, Lotz M (2004) Identification of mesenchymal progenitor cells in normal and osteoarthritic human articular cartilage. Arthritis Rheum 50(5):1522–1532PubMedCrossRefGoogle Scholar
  6. 6.
    Poole R, Blake S, Buschmann M, Goldring S, Laverty S, Lockwood S et al (2010) Recommendations for the use of preclinical models in the study and treatment of osteoarthritis. Osteoarthritis Cartilage 18(Suppl 3):S10–S16PubMedCrossRefGoogle Scholar
  7. 7.
    Srikanth VK, Fryer JL, Zhai G, Winzenberg TM, Hosmer D, Jones G (2005) A meta-analysis of sex differences prevalence, incidence and severity of osteoarthritis. Osteoarthritis Cartilage 13(9):769–781PubMedCrossRefGoogle Scholar
  8. 8.
    Spector TD, Nandra D, Hart DJ, Doyle DV (1997) Is hormone replacement therapy protective for hand and knee osteoarthritis in women?: The Chingford Study. Ann Rheum Dis 56(7):432–434PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Cirillo DJ, Wallace RB, Wu L, Yood RA (2006) Effect of hormone therapy on risk of hip and knee joint replacement in the Women’s Health Initiative. Arthritis Rheum 54(10):3194–3204PubMedCrossRefGoogle Scholar
  10. 10.
    de Klerk BM, Schiphof D, Groeneveld FP, Koes BW, van Osch GJ, van Meurs JB et al (2009) No clear association between female hormonal aspects and osteoarthritis of the hand, hip and knee: a systematic review. Rheumatology (Oxford) 48(9):1160–1165CrossRefGoogle Scholar
  11. 11.
    de Klerk BM, Schiphof D, Groeneveld FP, Koes BW, van Osch GJ, van Meurs JB et al (2009) Limited evidence for a protective effect of unopposed oestrogen therapy for osteoarthritis of the hip: a systematic review. Rheumatology (Oxford) 48(2):104–112CrossRefGoogle Scholar
  12. 12.
    Ma HL, Blanchet TJ, Peluso D, Hopkins B, Morris EA, Glasson SS (2007) Osteoarthritis severity is sex dependent in a surgical mouse model. Osteoarthritis Cartilage 15(6):695–700PubMedCrossRefGoogle Scholar
  13. 13.
    Mahr S, Menard J, Krenn V, Muller B (2003) Sexual dimorphism in the osteoarthritis of STR/ort mice may be linked to articular cytokines. Ann Rheum Dis 62(12):1234–1237PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    de Hooge AS, van de Loo FA, Bennink MB, Arntz OJ, de Hooge P, van den Berg WB (2005) Male IL-6 gene knock out mice developed more advanced osteoarthritis upon aging. Osteoarthritis Cartilage 13(1):66–73PubMedCrossRefGoogle Scholar
  15. 15.
    Hu K, Xu L, Cao L, Flahiff CM, Brussiau J, Ho K et al (2006) Pathogenesis of osteoarthritis-like changes in the joints of mice deficient in type IX collagen. Arthritis Rheum 54(9):2891–2900PubMedCrossRefGoogle Scholar
  16. 16.
    Xu L, Peng H, Glasson S, Lee PL, Hu K, Ijiri K et al (2007) Increased expression of the collagen receptor discoidin domain receptor 2 in articular cartilage as a key event in the pathogenesis of osteoarthritis. Arthritis Rheum 56(8):2663–2673PubMedCrossRefGoogle Scholar
  17. 17.
    Vasheghani F, Monemdjou R, Fahmi H, Zhang Y, Perez G, Blati M et al (2013) Adult Cartilage-Specific Peroxisome Proliferator-Activated Receptor Gamma Knockout Mice Exhibit the Spontaneous Osteoarthritis Phenotype. Am J Pathol 182(4):1099–1106PubMedCrossRefGoogle Scholar
  18. 18.
    Blom AB, van Lent PL, Libregts S, Holthuysen AE, van der Kraan PM, van Rooijen N et al (2007) Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3. Arthritis Rheum 56(1):147–157PubMedCrossRefGoogle Scholar
  19. 19.
    van der Kraan PM, Vitters EL, van de Putte LB, van den Berg WB (1989) Development of osteoarthritic lesions in mice by “metabolic” and “mechanical” alterations in the knee joints. Am J Pathol 135(6):1001–1014PubMedCentralPubMedGoogle Scholar
  20. 20.
    van Osch GJ, van der Kraan PM, Blankevoort L, Huiskes R, van den Berg WB (1996) Relation of ligament damage with site specific cartilage loss and osteophyte formation in collagenase induced osteoarthritis in mice. J Rheumatol 23(7):1227–1232PubMedGoogle Scholar
  21. 21.
    van Osch GJ, van der Kraan PM, van den Berg WB (1994) Site-specific cartilage changes in murine degenerative knee joint disease induced by iodoacetate and collagenase. J Orthop Res 12(2):168–175PubMedCrossRefGoogle Scholar
  22. 22.
    Ogbonna AC, Clark AK, Gentry C, Hobbs C, Malcangio M (2013) Pain-like behaviour and spinal changes in the monosodium iodoacetate model of osteoarthritis in C57Bl/6 mice. Eur J Pain 17(4):514–526PubMedCrossRefGoogle Scholar
  23. 23.
    Visco DM, Hill MA, Widmer WR, Johnstone B, Myers SL (1996) Experimental osteoarthritis in dogs: a comparison of the Pond-Nuki and medial arthrotomy methods. Osteoarthritis Cartilage 4(1):9–22PubMedCrossRefGoogle Scholar
  24. 24.
    Clements KM, Price JS, Chambers MG, Visco DM, Poole AR, Mason RM (2003) Gene deletion of either interleukin-1beta, interleukin-1beta-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(12):3452–3463PubMedCrossRefGoogle Scholar
  25. 25.
    Kamekura S, Hoshi K, Shimoaka T, Chung U, Chikuda H, Yamada T et al (2005) Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage 13(7):632–641PubMedCrossRefGoogle Scholar
  26. 26.
    Poole AR (1999) An introduction to the pathophysiology of osteoarthritis. Front Biosci 4:D662–D670PubMedCrossRefGoogle Scholar
  27. 27.
    Santori N, Villar RN (1999) Arthroscopic findings in the initial stages of hip osteoarthritis. Orthopedics 22(4):405–409PubMedGoogle Scholar
  28. 28.
    Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, Ma HL et al (2005) Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434(7033):644–648PubMedCrossRefGoogle Scholar
  29. 29.
    Glasson SS, Blanchet TJ, Morris EA (2007) The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthritis Cartilage 15(9):1061–1069PubMedCrossRefGoogle Scholar
  30. 30.
    Glasson SS, Askew R, Sheppard B, Carito BA, Blanchet T, Ma HL et al (2004) Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice. Arthritis Rheum 50(8):2547–2558PubMedCrossRefGoogle Scholar
  31. 31.
    Chia SL, Sawaji Y, Burleigh A, McLean C, Inglis J, Saklatvala J et al (2009) Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS-5 and delays cartilage degradation in murine osteoarthritis. Arthritis Rheum 60(7):2019–2027PubMedCrossRefGoogle Scholar
  32. 32.
    Moser M, Bosserhoff AK, Hunziker EB, Sandell L, Fassler R, Buettner R (2002) Ultrastructural cartilage abnormalities in MIA/CD-RAP-deficient mice. Mol Cell Biol 22(5):1438–1445PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Schmid R, Schiffner S, Opolka A, Grassel S, Schubert T, Moser M et al (2010) Enhanced cartilage regeneration in MIA/CD-RAP deficient mice. Cell Death Dis 1:e97PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Mankin HJ (1971) Biochemical and metabolic aspects of osteoarthritis. Orthop Clin North Am 2(1):19–31PubMedGoogle Scholar
  35. 35.
    Echtermeyer F, Bertrand J, Dreier R, Meinecke I, Neugebauer K, Fuerst M et al (2009) Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis. Nat Med 15(9):1072–1076PubMedCrossRefGoogle Scholar
  36. 36.
    Glasson SS, Chambers MG, van den Berg WB, Little CB (2010) The OARSI histopathology initiative—recommendations for histological assessments of osteoarthritis in the mouse. Osteoarthritis Cartilage 18(Suppl 3):S17–S23PubMedCrossRefGoogle Scholar
  37. 37.
    Botter SM, Glasson SS, Hopkins B, Clockaerts S, Weinans H, van Leeuwen JP et al (2009) 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(5):636–645PubMedCrossRefGoogle Scholar
  38. 38.
    Chambers MG, Bayliss MT, Mason RM (1997) Chondrocyte cytokine and growth factor expression in murine osteoarthritis. Osteoarthritis Cartilage 5(5):301–308PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Orthopaedic Surgery, Experimental Orthopaedics, Centre for Medical Biotechnology, BioPark IUniversity of RegensburgRegensburgGermany
  2. 2.Department of OrthopaedicsUniversity of RegensburgRegensburgGermany

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