Osteoarthritis (OA) is widely recognized is a pervasive disease marked by the destruction of articular cartilage. While the underlying causes of OA have been elusive they are probably heterogeneous in nature. In the last few years a thorough genetic analyses of certain families with OA secondary to chondrodysplasia, identification of mutations in the gene encoding cartilage oligomeric matrix protein (COMP) as the causative agent. These findings have led to the speculation that genes such as COMP may be responsible, in part, for the more sporadic forms of OA. However, to date the mechanism by which mutant COMP(s) leads to disease is unknown. In fact, the normal role that COMP plays in cartilage biology is also unknown, thus presenting a roadblock to our understanding of how COMP could participate in OA and in normal cartilage biology. Recently, by means of retroviral gene transfer method to ectopically express COMP in a novel in vitro chondrogenesis system consisting of high-density micromass cultures of a murine mesenchymal multi-potential cell line (C3H10t1/2), we observe that COMP over- expression enhances BMP2-induced chondrogenesis in vitro. Using this system, we propose to test the hypothesis that COMP functions to regulate mesenchymal chondrogenesis by examining the activities of wild-type and mutant COMP proteins of wild-type COMP in regulating chondrogenesis. The following Specific Aims will be addressed: 1) by retroviral gene transfer, test the role of wild-type COMP in regulating chondrogenesis pathway, i.e. cellular condensation, expression of matrix and regulatory genes, cellular phenotype and ultrastructure, and cell proliferation/apoptosis; 2) assess mutant COMP function in this system by characterizing the effects of retroviral gene transfer of mutant COMP genes; 3) assess the in vivo functions of both wild-type and mutant COMP by a) retroviral gene transfer into the developing chick limb bud and b) by generating mice expressing mutant COMP sequences by gene knock-in technology, and characterizing the resultant phenotype; and 4) examine the mechanistic basis of COMP function in chondrogenesis by identifying and characterizing candidate downstream genes by differential gene expression profiling resulting from exogenous COMP expression. Taken together, resulting from these studies should lead to a better understanding of the functional role of COMP in cartilage biology and in chondrodysplasia, and provide a rational basis for assessing the importance of COMP in the pathogenesis of OA.

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Thomas Jefferson University
United States
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