Abstract
Given the prevalence and the scope of the personal and societal burden of OA, investigators have become increasingly interested in understanding the pathogenic basis of disease and developing novel disease-modifying OA therapies. Because of the well-documented central role that joint trauma plays in the initiation of knee OA, large animal and rodent models of knee injury that accurately recapitulate the OA disease process have become increasingly widespread over the past decade. To enable study in the context of defined genetic backgrounds, investigative teams have informally developed standardized protocols for injuring the mouse knee that aim to induce a reproducible degenerative process both in terms of severity and temporal pacing of disease progression. One such procedure, the meniscal/ligamentous injury (MLI) model of posttraumatic OA, is described in detail in this chapter. The description provided here sets the stage for both inexperienced and established investigators to employ the MLI procedure, or other similar surgical destabilization methods, to initiate the development of posttraumatic OA in the mouse. Successful application of this method provides a preclinical platform to study the mechanisms driving the pathogenesis of OA and to develop chondroprotective/regenerative strategies to treat it.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
CDC (2009) Prevalence and most common causes of disability among adults – United States 2005. MMWR Morb Mortal Wkly Rep 58:421–426
Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, Liang MH, Kremers HM, Mayes MD, Merkel PA, Pillemer SR, Reveille JD, Stone JH (2008) Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I 2. Arthritis Rheum 58:15–25
Hootman JM, Helmick CG (2006) Projections of US prevalence of arthritis and associated activity limitations. Arthritis Rheum 54:226–229
Buckwalter JA, Mankin HJ, Grodzinsky AJ (2005) Articular cartilage and osteoarthritis. Instr Course Lect 54:465–480
Loughlin J, Dowling B, Chapman K, Marcelline L, Mustafa Z, Southam L, Ferreira A, Ciesielski C, Carson DA, Corr M (2004) Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc Natl Acad Sci U S A 101:9757–9762
Reynard LN, Loughlin J (2013) Insights from human genetic studies into the pathways involved in osteoarthritis. Nat Rev Rheumatol 9:573–583
Reynard LN, Loughlin J (2013) The genetics and functional analysis of primary osteoarthritis susceptibility. Exp Rev Mol Med 15:e2
Goldring MB, Marcu KB (2012) Epigenomic and microRNA-mediated regulation in cartilage development, homeostasis, and osteoarthritis. Trends Mol Med 18:109–118
Mooney RA, Sampson ER, Lerea J, Rosier RN, Zuscik MJ (2011) High-fat diet accelerates progression of osteoarthritis after meniscal/ligamentous injury. Arthritis Res Therap 13:R198
Griffin TM, Huebner JL, Kraus VB, Yan Z, Guilak F (2012) Induction of osteoarthritis and metabolic inflammation by a very high-fat diet in mice: effects of short-term exercise. Arthritis Rheum 64:443–453
Louer CR, Furman BD, Huebner JL, Kraus VB, Olson SA, Guilak F (2012) Diet-induced obesity significantly increases the severity of posttraumatic arthritis in mice. Arthritis Rheum 64:3220–3230
Vo N, Niedernhofer LJ, Nasto LA, Jacobs L, Robbins PD, Kang J, Evans CH (2013) An overview of underlying causes and animal models for the study of age-related degenerative disorders of the spine and synovial joints. J Orthop Res 31:831–837
Englund M (2010) The role of biomechanics in the initiation and progression of OA of the knee. Best Pract Res Clin Rheumatol 24:39–46
Roos H, Lauren M, Adalberth T, Roos EM, Jonsson K, Lohmander LS (1998) Knee osteoarthritis after meniscectomy: prevalence of radiographic changes after twenty-one years, compared with matched controls. Arthritis Rheum 41:687–693
Suzuki Y, Takeuchi N, Sagehashi Y, Yamaguchi T, Itoh H, Iwata H (1998) Effects of hyaluronic acid on meniscal injury in rabbits. Arch Orthop Trauma Surg 117:303–306
Goto H, Shuler FD, Niyibizi C, Fu FH, Robbins PD, Evans CH (2000) Gene therapy for meniscal injury: enhanced synthesis of proteoglycan and collagen by meniscal cells transduced with a TGFbeta(1)gene. Osteoarthritis Cartilage 8:266–271
Murphy JM, Fink DJ, Hunziker EB, Barry FP (2003) Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum 48:3464–3474
Janusz MJ, Bendele AM, Brown KK, Taiwo YO, Hsieh L, Heitmeyer SA (2002) Induction of osteoarthritis in the rat by surgical tear of the meniscus: inhibition of joint damage by a matrix metalloproteinase inhibitor. Osteoarthritis Cartilage 10:785–791
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 48:3452–3463
Kamekura S, Hoshi K, Shimoaka T, Chung U, Chikuda H, Yamada T, Uchida M, Ogata N, Seichi A, Nakamura K, Kawaguchi H (2005) Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage 13:632–641
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 434:644–648
Majumdar MK, Askew R, Schelling S, Stedman N, Blanchet T, Hopkins B, Morris EA, Glasson SS (2007) 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
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 60:3723–3733
Kamekura S, Kawasaki Y, Hoshi K, Shimoaka T, Chikuda H, Maruyama Z, Komori T, Sato S, Takeda S, Karsenty G, Nakamura K, Chung UI, Kawaguchi H (2006) 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
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 3:101ra193
Mapp PI, Walsh DA, Bowyer J, Maciewicz RA (2010) Effects of a metalloproteinase inhibitor on osteochondral angiogenesis, chondropathy and pain behavior in a rat model of osteoarthritis. Osteoarthritis Cartilage 18:593–600
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 19:315–323
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
Glasson SS, Askew R, Sheppard B, Carito BA, Blanchet T, Ma HL, Flannery CR, Kanki K, Wang E, Peluso D, Yang Z, Majumdar MK, Morris EA (2004) Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice. Arthritis Rheum 50:2547–2558
Sampson ER, Beck CA, Ketz J, Canary KL, Hilton MJ, Awad H, Schwarz EM, Chen D, O'Keefe RJ, Rosier RN, Zuscik MJ (2011) Establishment of an index with increased sensitivity for assessing murine arthritis. J Orthop Res 29(8):1145–1151
Gossan N, Zeef L, Hensman J, Hughes A, Bateman JF, Rowley L, Little CB, Piggins HD, Rattray M, Boot-Handford RP, Meng QJ (2013) The circadian clock in chondrocytes regulates genes controlling key aspects of cartilage homeostasis. Arthritis Rheum 65(9):2334–2345
Acknowledgements
We would like to thank Brittanie Kilchoer and Christopher Farnsworth for their outstanding assistance photographing the various surgical steps. Support for establishment of the MLI protocol and the assembly of this chapter was provided by a Clinical Priority Program (CPP) grant from AOTrauma International and from the following NIH grants: P50 AR054041, P30 AR061307, and T32 AR053459.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Hamada, D., Sampson, E.R., Maynard, R.D., Zuscik, M.J. (2014). Surgical Induction of Posttraumatic Osteoarthritis in the Mouse. In: Hilton, M. (eds) Skeletal Development and Repair. Methods in Molecular Biology, vol 1130. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-989-5_5
Download citation
DOI: https://doi.org/10.1007/978-1-62703-989-5_5
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-62703-988-8
Online ISBN: 978-1-62703-989-5
eBook Packages: Springer Protocols