TYPE II COLLAGEN GENE MUTATIONS IN OSTEOARTHRITIS

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The etiology of osteoarthritis (OA), is at present unknown. Genetic, environmental, metabolic and biomechanical factors have been suggested as playing possible roles.Interest in a genetic role for the etiology of OA has expanded based on clinical identification of positive inheritance patterns in certain disease sub-sets such as Heberden's nodes, differences in the prevalence of OA among different races and populations, increased frequency of OA in patients with HLA-A1B8 and HLA- B8 and the recent demonstration of a type-II collagen gene (COL2A1) mutation as a cause of primary generalized OA in at least one form of the disease, primary OA associated with a spinal chondrodysplasia. The mutation resulted in the replacement of arginine at position 519 of the a1(II) collagen molecule to cysteine, an amino acid not found in type-II collagen from humans or other species studied so far. Further studies in our laboratory have demonstrated the a1-519 mutation in an additional two of seven families studied. The studies proposed in this proposal will: (1) determine the prevalence of the a-519 mutation with strong family clustering of generalized OA and in non-related individuals with hip/knee OA; and identify other mutations in the COL2A1 gene; and (2) study body fluid biochemical markers of cartilage (collagen, proteoglycan) metabolism to assess OA etiopathologic mechanisms and clinical utility. The results of these studies will allow us to develop DNA probes; to delineate disease susceptibility of individuals to OA; and to correlate various gene defects with varying phenotypic patterns of disease severity. Assessment of biochemical markers of cartilage will add to our understanding of OA disease mechanisms.