Osteoarthritis-like changes in the heterozygous sedc mouse associated with the HtrA1-Ddr2-Mmp-13 degradative pathway: A new model of osteoarthritis

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Abstract

Objective: To test the hypothesis that the spondyloepiphyseal dysplasia congenita (. sedc) heterozygous (. sedc/+) mouse, a . COL2A1 mutant, is a model for the study of osteoarthritis (OA) in the absence of dwarfism and to investigate the presence of HtrA1, Ddr2, and Mmp-13 and their possible involvement in a universal mechanism leading to OA. Design: Whole mount skeletons of adult animals were analyzed to determine whether . sedc/+ mice exhibit dwarfism. To characterize progression of osteoarthritic degeneration over time, knee and temporomandibular joints from . sedc/+ and wild-type mice were analyzed histologically, and severity of articular cartilage degradation was graded using the Osteoarthritis Research Society International (OARSI) scoring system. Immunohistochemistry was used to detect changes in expression of HtrA1, Ddr2, and Mmp-13 in articular cartilage of knees. Results: As previously reported, the . sedc/+ skeleton morphology was indistinguishable from wild type, and skeletal measurements revealed no significant differences. The . sedc/+ mouse did, however, show significantly higher OARSI scores in knee (9, 12 and 18 months) and temporomandibular joints at all ages examined. Histological staining showed regions of proteoglycan degradation as early as 2 months in both temporomandibular and knee joints of the mutant. Cartilage fissuring and erosion were observed to begin between 2 and 6 months in temporomandibular joints and 9 months in knee joints from . sedc/+ mice. Immunohistochemistry of mutant knee articular cartilage showed increased expression of HtrA1, Ddr2, and Mmp-13 compared to wild type, which upregulation preceded fibrillation and fissuring of the articular surfaces. Conclusions: With regard to skeletal morphology, the . sedc/+ mouse appears phenotypically normal but develops premature OA as hypothesized. We conclude that the . sedc/+ mouse is a useful model for the study of OA in individuals with overtly normal skeletal structure and a predisposition for articular cartilage degeneration. © 2011 Osteoarthritis Research Society International.

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Holt, D. W., Henderson, M. L., Stockdale, C. E., Farrell, J. T., Kooyman, D. L., Bridgewater, L. C., & Seegmiller, R. E. (2012). Osteoarthritis-like changes in the heterozygous sedc mouse associated with the HtrA1-Ddr2-Mmp-13 degradative pathway: A new model of osteoarthritis. Osteoarthritis and Cartilage, 20(5), 430–439. https://doi.org/10.1016/j.joca.2011.11.008

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