MOLECULAR MECHANISMS OF SKELETOGENESIS

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DESCRIPTION: (Adapted from investigator's abstract) This grant request is designed to study the origin of the disease phenotype that develops in transgenic mice expressing a mutant type X collagen in addition to their normal endogenous type X collagen. Of particular interest is whether the mutant collagen molecules impair the function of the normal molecules via their participation in heterotypic collagen monomers and subsequent network within the growth plate, or whether the mutant molecules may independently affect the function of the growth plate chondrocytes (a gain of function phenotype). The work can be divided into 5 Specific Aims: 1) demonstrating that the mutant and normal collagen molecules are co-expressed and can interact in vivo; 2) determining the effect of the transgene phenotype in the absence of endogenous type X collagen expression; 3) determining the effect of transgene expression on growth plate chondrocyte proliferation, hypertrophy and apoptosis; 4) determining whether transgene expression affects the synthesis of other growth plate macromolecules; and 5) determining the effect of transgene expression on bone formation, resorption and mineral structure.