GDF REGULATION OF ENDOCHONDRAL BONE GROWTH

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DESCRIPTION (Taken from the application): In recent years, numerous advances have been made towards understanding the molecular regulation of chondrocyte maturation within the growth plate through the production of growth factors and the regulation of their receptors and receptor-mediated transmembrane signaling processes. The growth/differentiation factors (GDFs) represent a distinct subset of the TGF-beta family which may play a role in regulating endochondral bone growth. Evidence for GDF involvement comes largely from the documented mutation in GDF-5/CDMP-1 in individuals with acromesomelic chondrodysplasia of the Hunter-Thompson and Grebe types, and a reduction in the length of the long bones of GDF-5 deficient brachypodism mice. Given the link between GDF-5/CDMP-1 and chondrodysplasia in humans, it is likely that other chondrodysplastic disorders are linked to mutations in related GDF/CDMP family members. The goal of this research is to examine the effect of GDFs 5, 6, & 7 on endochondral bone growth by studying animals with a deficiency in these signaling peptides. We will examine mice with mutations in the genes which code for GDF 5, 6 or 7. For each gene of interest, three groups of ten healthy male mice will be studied, representing mutant (-/-) and heterozygous (+/-) control littermates at 4 weeks of age. Using classical methods of stereology and chondrocyte kinetics, growth plates from the proximal tibia, proximal humerus, and fourth rib will be carefully examined to test the hypothesis that mice deficient in GDF 5, 6, or 7 will exhibit impaired endochondral bone growth. The proposed detailed analyses of stereologic and chondrocyte kinetic parameters will help to identify precisely which growth plate cell populations are affected by the absence of GDFs 5, 6, & 7. Future studies will extend these investigations to double and triple GDF family member mutations, as well as molecular characterization of other important growth plate signaling molecules in the various single, double, and triple GDF mutations.