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The degenerative processes that lead to destruction of articular cartilage in osteoarthritis represent a final common of these factors are, and how specific factors contribute to the degradative processes seen in osteoarthritis, is clearly necessary before one can design optimal therapeutic approaches to stop or slow down the development of osteoarthritis.

Hereditary factors have been implicated for several types of osteoarthritis in which multiple joints are affected, including Heberden's nodes, Nodal primary generalized osteoarthritis and Non-nodal primary generalized osteoarthritis. Taken together, these account for a significant proportion of symptomatic disease. The systemic involvement observed in these disorders suggested that hereditary alterations in constitutively expressed cartilage proteins were likely to be among the factors contributing to their pathogenesis. A preponderance of evidence now identifies alterations in the quantitatively minor cartilage collagens IX and XI as likely genetic determinants for several types of osteoarthritis. Such evidence includes the 1) occurrence of osteoarthritis in mice having mutations in these genes, 2) the identification of families in whom precocious osteoarthritis has either been linked to these genes or shown to be associated with mutations in these genes, and 3) data suggesting a linkage association between these genes and sibpairs concordant for nodal primary generalized osteoarthritis.

Our objective is to determine how alterations in these two cartilage collagens contribute to the pathogenesis of osteoarthritis. One specific aim involves the study of patients having known collagen IX and XI mutations at the mRNA, protein, and histological levels using cartilage biopsy material for RNA and protein isolation, chondrocyte culture, immunohistochemistry and electron microscopy. Our second aim is to identify additional osteoarthritis associated mutations and polymorphisms within these genes by studying individuals most likely to have alterations at these loci. These individuals include 1) patients from families already linked to these loci, 2) patients with phenotypes similar to those for which mutations have already been identified, and 3) patients with forms of osteoarthritis suggested by sib-pair analysis, extended pedigree analysis, or allelic association analysis to be associated with these loci.

Characterizing the effects of known mutations upon cartilage, and identifying new mutations and polymorphisms associated with osteoarthritis phenotypes, will help us understand the roles of these proteins in cartilage and the means by which their alterations contribute to the degradative processes of osteoarthritis.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.