Degeneration of synovial joint cartilage in the form of osteoarthritis (OA) is one of the leading causes of chronic disability, yet the molecular pathogenesis of OA is poorly understood. Therefore, the development and study of appropriate animal models is needed. The Disproportionate micromelia (Dmm) and spondyloepiphyseal dysplasia congenita (sedc) mouse strains are the result of mutations in the type II fibrillar collagen gene, whereas the chondrodysplasia (cho) mouse strain is the result of a mutation in the type XI fibrillar collagen gene, and all three are characterized by skeletal dysplasia. Though they result from different classes of mutations and have different skeletal phenotypes, all three mutants exhibit similar early-onset degeneration of knee-joint cartilage. Accordingly, we hypothesize that murine OA proceeds through common pathological pathways even though the degeneration may be initiated by different types of insults. To test this hypothesis and to identify the biomolecular changes that are coincident with OA and common to these three murine models, the following specific aims are proposed: 1) to characterize OA in sedc knee and temporomandibular joint (TMJ) articular cartilage histologically and ultrastructurally;2) to identify common patterns of articular cartilage degeneration leading to OA in both knee and TMJ of the three mutants using biomarkers of cartilage degeneration and chondrocyte apoptosis;and 3) to determine whether the Dmm, sedc, and cho mutations cause ER stress that is severe enough to trigger the unfolded protein response (UPR) in developing articular cartilage, and whether that UPR activates inflammation or apoptosis pathways. Histochemistry will detect qualitative changes in cartilage matrix macromolecules, and immunohistochemistry will document the appearance of OA biomarkers (DDR-2, MMP-3, MMP-13, COL2-3/4m antibody, NITEGE and VDIPEN) and programmed cell death, all in relation to initiation of histopathological changes. Evidence of an ER stress response in the heterozygotes of these mutants would suggest that unfolded proteins are being retained in the cells and that continuous ER stress during cartilage development may contribute to the early-onset OA phenotype. This observation would thus become a new area of investigation in OA. Identification of changes that are common to all three mouse models will be the key to our success. These putative universal pathological pathways may represent new targets for therapeutic intervention and molecular markers for diagnosis of disease.
This study in three murine models will provide biomolecular insight into the pathogenesis of OA and pave the way for future investigations into the use of various drug and gene-based therapies.
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