GDF Modulation of Tendon Maintenance and Repair

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DESCRIPTION (provided by applicant): Clinically, growth factors such as the growth/differentiation factors (GDFs) represent a unique potential for the treatment of tendon injuries. To administer these agents effectively in a clinical setting, a complete understanding of their mechanisms of action in tendon maintenance and repair is essential. Our previous work on the GDF-5 deficient brachypodism mouse has demonstrated that GDF-5 deficiency results in altered tendon composition, ultrastructure and mechanical behavior, as well as a delay in Achilles tendon healing. Together with GDF-5, GDF-6 and GDF-7 form a subfamily of related GDF proteins. Recently, knockout mouse models have been developed in which the genes for GDF-6 and GDF-7 have been modified. These two animal models provide further unique experimental systems for examining the role of GDFs in mammals. The goal of this research is to examine the effects of GDF-6 and GDF-7 on tendon maintenance and repair. Understanding the in vivo roles of these proteins will allow this family of growth factors to be considered for therapeutic use in tendon healing. In the first set of experiments, the roles of GDF-6 and GDF-7 in the establishment of normal tendon structure and function will be examined. Mechanical properties of Achilles tendons from male and female 16 week-old GDF-6 or GDF-7 deficient mice will be obtained from tensile mechanical tests and compared to wild-type control littermates. To explain differences in mechanical properties, histological, ultrastructural, compositional, and molecular characterization will be performed using standard techniques of molecular biology, biochemistry, and light and transmission electron microscopy. In the second set of experiments, the roles of GDF-6 and GDF-7 in tendon repair will be examined. Mid-substance tenotomies of the Achilles tendon will be performed in 16-week-old mice. The histologic, compositional, and molecular response will be characterized after 3, 5, 7, 9, 14, 28, 42, and 84 days. Tendon ultrastructure and mechanical integrity will be examined at 1, 2, 4, 6, and 12 weeks after tenotomy. The proposed experiments will provide the necessary baseline characterization of tendon properties in GDF-6 and GDF-7 deficient mice, as well as elucidate the short and long-term healing response to Achilles tendon injury. These studies combine to enhance our understanding of the mechanisms of action of GDFs in tendon maintenance and repair.