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Mouse Models of Osteoarthritis: Surgical Model of Posttraumatic Osteoarthritis Induced by Destabilization of the Medial Meniscus

  • Kirsty L. Culley
  • Cecilia L. Dragomir
  • Jun Chang
  • Elisabeth B. Wondimu
  • Jonathan Coico
  • Darren A. Plumb
  • Miguel Otero
  • Mary B. Goldring
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1226)

Abstract

The surgical model of destabilization of the medial meniscus (DMM) has become a gold standard for studying the onset and progression of posttraumatic osteoarthritis (OA). The DMM model mimics clinical meniscal injury, a known predisposing factor for the development of human OA, and permits the study of structural and biological changes over the course of the disease. In addition, when applied to genetically modified or engineered mouse models, this surgical procedure permits dissection of the relative contribution of a given gene to OA initiation and/or progression. This chapter describes the requirements for the surgical induction of OA in mouse models, and provides guidelines and tools for the subsequent histological, immunohistochemical, and molecular analyses. Methods for the assessment of the contributions of selected genes in genetically modified strains are also provided.

Key words

Surgical model Histology Immunohistochemistry RNA extraction 

Notes

Acknowledgements

Research related to this topic is supported by National Institutes of Health grants R01-AG-022021 and RC4-AR060546.

References

  1. 1.
    Poulet B, Ulici V, Stone TC et al (2012) Time-series transcriptional profiling yields new perspectives on susceptibility to murine osteoarthritis. Arthritis Rheum 64:3256–3266PubMedCrossRefGoogle Scholar
  2. 2.
    Poulet B, Hamilton RW, Shefelbine S et al (2011) Characterizing a novel and adjustable noninvasive murine joint loading model. Arthritis Rheum 63:137–147PubMedCrossRefGoogle Scholar
  3. 3.
    Ko FC, Dragomir C, Plumb DA et al (2013) In vivo cyclic compression causes cartilage degeneration and subchondral bone changes in mouse tibiae. Arthritis Rheum 65:1569–1578PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Sato T, Konomi K, Yamasaki S et al (2006) Comparative analysis of gene expression profiles in intact and damaged regions of human osteoarthritic cartilage. Arthritis Rheum 54:808–817PubMedCrossRefGoogle Scholar
  5. 5.
    Aigner T, Fundel K, Saas J et al (2006) Large-scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis. Arthritis Rheum 54: 3533–3544PubMedCrossRefGoogle Scholar
  6. 6.
    Glasson SS (2007) In vivo osteoarthritis target validation utilizing genetically-modified mice. Curr Drug Targets 8:367–376PubMedCrossRefGoogle Scholar
  7. 7.
    Little CB, Fosang AJ (2010) Is cartilage matrix breakdown an appropriate therapeutic target in osteoarthritis–insights from studies of aggrecan and collagen proteolysis? Curr Drug Targets 11:561–575PubMedCrossRefGoogle Scholar
  8. 8.
    Bernardo BC, Belluoccio D, Rowley L et al (2011) Cartilage intermediate layer protein 2 (CILP-2) is expressed in articular and meniscal cartilage and down-regulated in experimental osteoarthritis. J Biol Chem 286:37758–37767PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Yasuhara R, Ohta Y, Yuasa T et al (2011) Roles of beta-catenin signaling in phenotypic expression and proliferation of articular cartilage superficial zone cells. Lab Invest 91:1739–1752PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Lodewyckx L, Cailotto F, Thysen S et al (2012) Tight regulation of wingless-type signaling in the articular cartilage - subchondral bone biomechanical unit: transcriptomics in Frzb-knockout mice. Arthritis Res Ther 14:R16PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Loeser RF, Olex AL, McNulty MA et al (2012) Microarray analysis reveals age-related differences in gene expression during the development of osteoarthritis in mice. Arthritis Rheum 64:705–717PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Nuka S, Zhou W, Henry SP et al (2010) Phenotypic characterization of epiphycan-deficient and epiphycan/biglycan double-deficient mice. Osteoarthritis Cartilage 18: 88–96PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Glasson SS, Askew R, Sheppard B et al (2005) Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434:644–648PubMedCrossRefGoogle Scholar
  14. 14.
    Stanton H, Rogerson FM, East CJ et al (2005) ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434: 648–652PubMedCrossRefGoogle Scholar
  15. 15.
    Little CB, Barai A, Burkhardt D et al (2009) Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum 60:3723–3733PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Echtermeyer F, Bertrand J, Dreier R et al (2009) Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis. Nat Med 15:1072–1076PubMedCrossRefGoogle Scholar
  17. 17.
    Lin AC, Seeto BL, Bartoszko JM et al (2009) Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med 15: 1421–1425PubMedCrossRefGoogle Scholar
  18. 18.
    Sampson ER, Hilton MJ, Tian Y et al (2011) Teriparatide as a chondroregenerative therapy for injury-induced osteoarthritis. Sci Transl Med 3:101ra193CrossRefGoogle Scholar
  19. 19.
    Chockalingam PS, Sun W, Rivera-Bermudez MA et al (2011) Elevated aggrecanase activity in a rat model of joint injury is attenuated by an aggrecanase specific inhibitor. Osteoarthritis Cartilage 19:315–323PubMedCrossRefGoogle Scholar
  20. 20.
    Johnson K, Zhu S, Tremblay MS et al (2012) A stem cell-based approach to cartilage repair. Science 336:717–721PubMedCrossRefGoogle Scholar
  21. 21.
    Rai MF, Hashimoto S, Johnson EE et al (2012) Heritability of articular cartilage regeneration and its association with ear-wound healing. Arthritis Rheum 64:2300–2310PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Hashimoto S, Rai MF, Janiszak KL et al (2012) Cartilage and bone changes during development of post-traumatic osteoarthritis in selected LGXSM recombinant inbred mice. Osteoarthritis Cartilage 20:562–571PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Nakamura E, Nguyen MT, Mackem S (2006) Kinetics of tamoxifen-regulated Cre activity in mice using a cartilage-specific CreER(T) to assay temporal activity windows along the proximodistal limb skeleton. Dev Dyn 235: 2603–2612PubMedCrossRefGoogle Scholar
  24. 24.
    Dao DY, Jonason JH, Zhang Y et al (2012) Cartilage-specific beta-catenin signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development. J Bone Miner Res 27:1680–1694PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Henry SP, Jang CW, Deng JM et al (2009) Generation of aggrecan-CreERT2 knockin mice for inducible Cre activity in adult cartilage. Genesis 47:805–814PubMedCentralPubMedGoogle Scholar
  26. 26.
    Henry SP, Liang S, Akdemir KC et al (2012) The postnatal role of Sox9 in cartilage. J Bone Miner Res 27:2511–2525PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Gossen M, Bujard H (1992) Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci U S A 89:5547–5551PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Grover J, Roughley PJ (2006) Generation of a transgenic mouse in which Cre recombinase is expressed under control of the type II collagen promoter and doxycycline administration. Matrix Biol 25:158–165PubMedCrossRefGoogle Scholar
  29. 29.
    Xu L, Polur I, Servais JM et al (2011) Intact pericellular matrix of articular cartilage is required for unactivated discoidin domain receptor 2 in the mouse model. Am J Pathol 179:1338–1346PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    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 15:1061–1069PubMedCrossRefGoogle Scholar
  31. 31.
    Flecknell PA (1996) Laboratory animal anesthesia. Academic, LondonGoogle Scholar
  32. 32.
    Glasson SS, Chambers MG, Van Den Berg WB et al (2010) The OARSI histopathology initiative—recommendations for histological assessments of osteoarthritis in the mouse. Osteoarthritis Cartilage 18(Suppl 3):S17–S23PubMedCrossRefGoogle Scholar
  33. 33.
    Loeser RF, Olex AL, McNulty MA et al (2013) Disease progression and phasic changes in gene expression in a mouse model of osteoarthritis. PLoS One 8:e54633PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Jenkins WL (1987) Pharmacologic aspects of analgesic drugs in animals: an overview. J Am Vet Med Assoc 191:1231–1240PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media. New York 2015

Authors and Affiliations

  • Kirsty L. Culley
    • 1
    • 2
  • Cecilia L. Dragomir
    • 1
  • Jun Chang
    • 1
    • 2
  • Elisabeth B. Wondimu
    • 1
    • 2
  • Jonathan Coico
    • 1
    • 2
  • Darren A. Plumb
    • 3
  • Miguel Otero
    • 1
    • 2
  • Mary B. Goldring
    • 1
    • 2
  1. 1.Tissue Engineering Regeneration and Repair Program, Research DivisionThe Hospital for Special SurgeryNew YorkUSA
  2. 2.Weill Cornell Medical CollegeNew YorkUSA
  3. 3.Breakthrough Breast Cancer Research UnitKing’s College London School of Medicine, Guy’s HospitalLondonUK

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