David Holt and Drs. L.C. Bridgewater and R.E. Seegmiller

Summary

Objective: To test the hypothesis that the spondyloepiphesial dysplasia congenita (sedc) heterozygous (sedc/þ) 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/þ mice exhibit dwarfism. To characterize progression of osteoarthritic degeneration over time, knee and temporomandibular joints from sedc/þ and wild-type mice were analyzed histologically, and severity of Q2 articular cartilage degradation was graded using the 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/þ skeleton morphology was indistinguishable fromwild type, and skeletal measurements revealed no significant differences. The sedc/þ mouse did, however, show significantly higherOARSI scores in knee (9,12 and 18months) 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 erosionwere observed to begin between 2 and 6 months in temporomandibular joints and 9 months in knee joints from sedc/þ 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/þ mouse appears phenotypically normal but develops premature OA as hypothesized. We conclude that the sedc/þ mouse is a useful model for the study of OA in individuals with overtly normal skeletal structure and a predisposition for articular cartilage degeneration.

To read complete article go to OARSI Article YJOCA2533_proof – 9 December 2011 – 1/10. Complete title is as follows: “Osteoarthritis-like changes in the heterozygous sedc mouse associated with the HtrA1eDdr2eMmp-13 degradative pathway: a new model of osteoarthritis”