Skip to main content
SpringerLink
Log in

Mouse Models of Osteoarthritis: Surgical Model of Post-traumatic Osteoarthritis Induced by Destabilization of the Medial Meniscus

  • Protocol
  • First Online:
Osteoporosis and Osteoarthritis

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2221))

Abstract

The surgical model of destabilization of the medial meniscus (DMM) has become a gold standard for studying the onset and progression of post-traumatic 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.

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

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Poulet B, Ulici V, Stone TC, Pead M, Gburcik V, Constantinou E, Palmer DB, Beier F, Timmons JA, Pitsillides AA (2012) Time-series transcriptional profiling yields new perspectives on susceptibility to murine osteoarthritis. Arthritis Rheum 64(10):3256–3266. https://doi.org/10.1002/art.34572

    Article  CAS  PubMed  Google Scholar 

  2. Poulet B, Hamilton RW, Shefelbine S, Pitsillides AA (2011) Characterizing a novel and adjustable noninvasive murine joint loading model. Arthritis Rheum 63(1):137–147. https://doi.org/10.1002/art.27765

    Article  PubMed  Google Scholar 

  3. Ko FC, Dragomir C, Plumb DA, Goldring SR, Wright TM, Goldring MB, van der Meulen MC (2013) In vivo cyclic compression causes cartilage degeneration and subchondral bone changes in mouse tibiae. Arthritis Rheum 65(6):1569–1578. https://doi.org/10.1002/art.37906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sato T, Konomi K, Yamasaki S, Aratani S, Tsuchimochi K, Yokouchi M, Masuko-Hongo K, Yagishita N, Nakamura H, Komiya S, Beppu M, Aoki H, Nishioka K, Nakajima T (2006) Comparative analysis of gene expression profiles in intact and damaged regions of human osteoarthritic cartilage. Arthritis Rheum 54(3):808–817

    Article  CAS  Google Scholar 

  5. Aigner T, Fundel K, Saas J, Gebhard PM, Haag J, Weiss T, Zien A, Obermayr F, Zimmer R, Bartnik E (2006) Large-scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis. Arthritis Rheum 54(11):3533–3544

    Article  CAS  Google Scholar 

  6. Glasson SS (2007) In vivo osteoarthritis target validation utilizing genetically-modified mice. Curr Drug Targets 8(2):367–376

    Article  CAS  Google Scholar 

  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(5):561–575. https://doi.org/10.2174/138945010791011956

    Article  CAS  PubMed  Google Scholar 

  8. Bernardo BC, Belluoccio D, Rowley L, Little CB, Hansen U, Bateman JF (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(43):37758–37767. https://doi.org/10.1074/jbc.M111.248039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yasuhara R, Ohta Y, Yuasa T, Kondo N, Hoang T, Addya S, Fortina P, Pacifici M, Iwamoto M, Enomoto-Iwamoto M (2011) Roles of beta-catenin signaling in phenotypic expression and proliferation of articular cartilage superficial zone cells. Lab Investig 91(12):1739–1752. https://doi.org/10.1038/labinvest.2011.144

    Article  CAS  PubMed  Google Scholar 

  10. Lodewyckx L, Cailotto F, Thysen S, Luyten FP, Lories RJ (2012) Tight regulation of wingless-type signaling in the articular cartilage - subchondral bone biomechanical unit: transcriptomics in Frzb-knockout mice. Arthritis Res Ther 14(1):R16. https://doi.org/10.1186/ar3695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Loeser RF, Olex AL, McNulty MA, Carlson CS, Callahan MF, Ferguson CM, Chou J, Leng X, Fetrow JS (2012) Microarray analysis reveals age-related differences in gene expression during the development of osteoarthritis in mice. Arthritis Rheum 64(3):705–717. https://doi.org/10.1002/art.33388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Nuka S, Zhou W, Henry SP, Gendron CM, Schultz JB, Shinomura T, Johnson J, Wang Y, Keene DR, Ramirez-Solis R, Behringer RR, Young MF, Hook M (2010) Phenotypic characterization of epiphycan-deficient and epiphycan/biglycan double-deficient mice. Osteoarthritis Cartilage 18(1):88–96. https://doi.org/10.1016/j.joca.2009.11.006

    Article  CAS  PubMed  Google Scholar 

  13. Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, Ma HL, Flannery CR, Peluso D, Kanki K, Yang Z, Majumdar MK, Morris EA (2005) Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434(7033):644–648

    Article  CAS  Google Scholar 

  14. Stanton H, Rogerson FM, East CJ, Golub SB, Lawlor KE, Meeker CT, Little CB, Last K, Farmer PJ, Campbell IK, Fourie AM, Fosang AJ (2005) ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434(7033):648–652

    Article  CAS  Google Scholar 

  15. Little CB, Barai A, Burkhardt D, Smith SM, Fosang AJ, Werb Z, Shah M, Thompson EW (2009) Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum 60(12):3723–3733

    Article  CAS  Google Scholar 

  16. Wondimu EB, Culley KL, Quinn J, Chang J, Dragomir CL, Plumb DA, Goldring MB, Otero M (2018) Elf3 contributes to cartilage degradation in vivo in a surgical model of post-traumatic osteoarthritis. Sci Rep 8(1):6438. https://doi.org/10.1038/s41598-018-24695-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Culley KL, Lessard SG, Green JD, Quinn J, Chang J, Khilnani T, Wondimu EB, Dragomir CL, Marcu KB, Goldring MB, Otero M (2019) Inducible knockout of CHUK/IKKalpha in adult chondrocytes reduces progression of cartilage degradation in a surgical model of osteoarthritis. Sci Rep 9(1):8905. https://doi.org/10.1038/s41598-019-45334-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ismail HM, Miotla-Zarebska J, Troeberg L, Tang X, Stott B, Yamamoto K, Nagase H, Fosang AJ, Vincent TL, Saklatvala J (2016) Brief report: JNK-2 controls aggrecan degradation in murine articular cartilage and the development of experimental osteoarthritis. Arthritis Rheumatol 68(5):1165–1171. https://doi.org/10.1002/art.39547

    Article  CAS  PubMed  Google Scholar 

  19. Rowe MA, Harper LR, McNulty MA, Lau AG, Carlson CS, Leng L, Bucala RJ, Miller RA, Loeser RF (2017) Reduced osteoarthritis severity in aged mice with deletion of macrophage migration inhibitory factor. Arthritis Rheumatol 69(2):352–361. https://doi.org/10.1002/art.39844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Miotla Zarebska J, Chanalaris A, Driscoll C, Burleigh A, Miller RE, Malfait AM, Stott B, Vincent TL (2017) CCL2 and CCR2 regulate pain-related behaviour and early gene expression in post-traumatic murine osteoarthritis but contribute little to chondropathy. Osteoarthritis Cartilage 25(3):406–412. https://doi.org/10.1016/j.joca.2016.10.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hwang SM, Feigenson M, Begun DL, Shull LC, Culley KL, Otero M, Goldring MB, Ta LE, Kakar S, Bradley EW, Westendorf JJ (2018) Phlpp inhibitors block pain and cartilage degradation associated with osteoarthritis. J Orthop Res 36(5):1487–1497. https://doi.org/10.1002/jor.23781

    Article  CAS  PubMed  Google Scholar 

  22. Holyoak DT, Chlebek C, Kim MJ, Wright TM, Otero M, van der Meulen MCH (2019) Low-level cyclic tibial compression attenuates early osteoarthritis progression after joint injury in mice. Osteoarthritis Cartilage 27(10):1526–1536. https://doi.org/10.1016/j.joca.2019.06.005

    Article  CAS  PubMed  Google Scholar 

  23. Echtermeyer F, Bertrand J, Dreier R, Meinecke I, Neugebauer K, Fuerst M, Lee YJ, Song YW, Herzog C, Theilmeier G, Pap T (2009) Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis. Nat Med 15(9):1072–1076. http://www.nature.com/nm/journal/v15/n9/suppinfo/nm.1998_S1.html

    Article  CAS  Google Scholar 

  24. Lin AC, Seeto BL, Bartoszko JM, Khoury MA, Whetstone H, Ho L, Hsu C, Ali AS, Alman BA (2009) Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med 15(12):1421–1425

    Article  CAS  Google Scholar 

  25. Sampson ER, Hilton MJ, Tian Y, Chen D, Schwarz EM, Mooney RA, Bukata SV, O'Keefe RJ, Awad H, Puzas JE, Rosier RN, Zuscik MJ (2011) Teriparatide as a chondroregenerative therapy for injury-induced osteoarthritis. Sci Transl Med 3(101):101ra193. https://doi.org/10.1126/scitranslmed.3002214

    Article  CAS  Google Scholar 

  26. Chockalingam PS, Sun W, Rivera-Bermudez MA, Zeng W, Dufield DR, Larsson S, Lohmander LS, Flannery CR, Glasson SS, Georgiadis KE, Morris EA (2011) Elevated aggrecanase activity in a rat model of joint injury is attenuated by an aggrecanase specific inhibitor. Osteoarthritis Cartilage 19(3):315–323. https://doi.org/10.1016/j.joca.2010.12.004

    Article  CAS  PubMed  Google Scholar 

  27. Johnson K, Zhu S, Tremblay MS, Payette JN, Wang J, Bouchez LC, Meeusen S, Althage A, Cho CY, Wu X, Schultz PG (2012) A stem cell-based approach to cartilage repair. Science 336(6082):717–721. https://doi.org/10.1126/science.1215157

    Article  CAS  PubMed  Google Scholar 

  28. Rai MF, Hashimoto S, Johnson EE, Janiszak KL, Fitzgerald J, Heber-Katz E, Cheverud JM, Sandell LJ (2012) Heritability of articular cartilage regeneration and its association with ear-wound healing. Arthritis Rheum 64:2300. https://doi.org/10.1002/art.34396

    Article  PubMed  PubMed Central  Google Scholar 

  29. Hashimoto S, Rai MF, Janiszak KL, Cheverud JM, Sandell LJ (2012) Cartilage and bone changes during development of post-traumatic osteoarthritis in selected LGXSM recombinant inbred mice. Osteoarthritis Cartilage 20(6):562–571. https://doi.org/10.1016/j.joca.2012.01.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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(9):2603–2612. https://doi.org/10.1002/dvdy.20892

    Article  CAS  PubMed  Google Scholar 

  31. Dao DY, Jonason JH, Zhang Y, Hsu W, Chen D, Hilton MJ, O'Keefe RJ (2012) Cartilage-specific beta-catenin signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development. J Bone Min Res 27(8):1680–1694. https://doi.org/10.1002/jbmr.1639

    Article  CAS  Google Scholar 

  32. Henry SP, Jang CW, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B (2009) Generation of aggrecan-CreERT2 knockin mice for inducible Cre activity in adult cartilage. Genesis 47(12):805–814. https://doi.org/10.1002/dvg.20564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Henry SP, Liang S, Akdemir KC, de Crombrugghe B (2012) The postnatal role of Sox9 in cartilage. J Bone Min Res 27(12):2511–2525. https://doi.org/10.1002/jbmr.1696

    Article  CAS  Google Scholar 

  34. 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(12):5547–5551

    Article  CAS  Google Scholar 

  35. 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(3):158–165. https://doi.org/10.1016/j.matbio.2005.11.003

    Article  CAS  PubMed  Google Scholar 

  36. Xu L, Polur I, Servais JM, Hsieh S, Lee PL, Goldring MB, Li Y (2011) Intact pericellular matrix of articular cartilage is required for unactivated discoidin domain receptor 2 in the mouse model. Am J Pathol 179(3):1338–1346. https://doi.org/10.1016/j.ajpath.2011.05.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Glasson SS, Blanchet TJ, Morris EA (2007) The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthr Cartil 15(9):1061–1069

    Article  CAS  Google Scholar 

  38. 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):695–700. https://doi.org/10.1016/j.joca.2006.11.005

    Article  PubMed  Google Scholar 

  39. Flecknell PA (1996) Laboratory animal anesthesia, 2nd edn. Academic Press, London

    Google Scholar 

  40. 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–S23. https://doi.org/10.1016/j.joca.2010.05.025

    Article  PubMed  Google Scholar 

  41. Loeser RF, Olex AL, McNulty MA, Carlson CS, Callahan M, Ferguson C, Fetrow JS (2013) Disease progression and phasic changes in gene expression in a mouse model of osteoarthritis. PLoS One 8(1):e54633. https://doi.org/10.1371/journal.pone.0054633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jenkins WL (1987) Pharmacologic aspects of analgesic drugs in animals: an overview. J Am Vet Med Assoc 191(10):1231–1240

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Research related to this topic was supported by National Institutes of Health grants R21-AG049980, R01-AG022021, and RC4-AR060546. Kirsty L. Culley, Purva Singh, Mary B. Goldring, and Miguel Otero contributed equally to this work.

Author information

Author notes

  1. Kirsty L. Culley, Purva Singh, Mary B. Goldring, and Miguel Otero contributed equally to this work.

Authors and Affiliations

  1. Orthopedic Soft Tissue Research Program, HSS Research Institute, The Hospital for Special Surgery, New York, NY, USA

    Kirsty L. Culley, Purva Singh, Samantha Lessard, Mengying Wang, Brennan Rourke, Mary B. Goldring & Miguel Otero

Authors
  1. Kirsty L. Culley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Purva Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samantha Lessard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mengying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Brennan Rourke
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mary B. Goldring
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Miguel Otero
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Miguel Otero .

Editor information

Editors and Affiliations

  1. Stem Cell Therapy and Skeletal Regeneration Lab, Mayo Clinic, Rochester, MN, USA

    Andre J. van Wijnen

  2. Stem Cell Therapy and Skeletal Regeneration Lab, Mayo Clinic, Rochester, MN, USA

    Marina S. Ganshina

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Culley, K.L. et al. (2021). Mouse Models of Osteoarthritis: Surgical Model of Post-traumatic Osteoarthritis Induced by Destabilization of the Medial Meniscus. In: van Wijnen, A.J., Ganshina, M.S. (eds) Osteoporosis and Osteoarthritis. Methods in Molecular Biology, vol 2221. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0989-7_14

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-0989-7_14

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-0988-0

  • Online ISBN: 978-1-0716-0989-7

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation