The overall aim of the present proposal is to carry out experiments in transgenic mice on the possible genetic causes of OA that cannot be carried out with human subjects. The experiments will address two questions: (a) Is there a close correlation between the dystrophic changes in cartilage of young mice and the severity of OA in adult mice with mutations in collagen genes expressed in cartilage? (B) Do mutations in collagen genes that cause cartilage disorders modify each other so that the severity of the defects caused by a mutation in one collagen gene are increased by coinheritance of mutations in a second collagen gene? If we find there is a correlation between late onset OA and early dystrophic changes, the results will support the evidence we have obtained from studies on one family (see Preliminary Results) that suggests X-ray examinations of young individuals can be used to predict the development of early onset OA in some families with heritable forms of the disease. If we find that mutations in two collagen genes can modify each other, they will help explain the difficulty that we and others have encountered in establishing Mendelian inheritance in many families with OA. We propose to use lines of transgenic mice already prepared by us and our collaborations as well as several additional lines we will prepare to pursue the following Specific Aims: A. Determine whether there is a correlation between (1) qualitative and quantitative assays for dystrophic changes in cartilage of young mice and (2) the severity of OA in adult mice in transgenic lines of mice with knock-out mutations in three collagen genes expressed in cartilage (Col2a1, Col9a1 and Col11a2). B. Determine whether the mild cartilage phenotypes produced by inactive alleles for each of the four collagens become more severe phenotypes when coinherited with an inactive allele for a second collagen gene expressed in cartilage. C. Determine whether the cartilage phenotypes produced by dominant negative alleles of the COL2A1 gene become more severe when coinherited with an inactive allele or a second dominant negative allele.
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