Clinically, growth factors such as the growth and 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. As the first viable in vivo animal model with a null mutation in one of the GDF genes, the brachypodism mouse mutant provides a unique experimental system for examining the role of GDFs in mammals. The goal of this research is to examine the effects of GDF-5 on tendon maintenance and healing. Understanding the in vivo role of GDF-5 will allow this family of growth factors to be considered for therapeutic use in tendon repair. Baseline characterization of Achilles tendon will be examined in the brachypodism mouse, which has a known null mutation in the gene for GDF-5. Mice with the same genetic background but with two normal GDF-5 alleles will serve as controls. The proposed experiments will provide the necessary baseline characterization of tendon properties in brachypod and control 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. In the first set of experiments, the role of GDF-5 in the establishment of normal tendon biomechanical properties will be examined. Mechanical properties of Achilles tendons from 6-week-old brachypod mice will be obtained from tensile mechanical tests and compared to controls. To explain differences in mechanical properties, histologic, compositional, molecular and ultrastructural characterization will be assessed using standard techniques of molecular biology, biochemistry, and light and transmission electron microscopy. In the second set of experiments, the role of GDF-5 in tendon repair will be examined. Mid-substance tenotomies of the Achilles tendon will be created in 6-week-old mice. The histologic, compositional, molecular, and ultrastructural response will be characterized after 3, 5, 7, 9, 11, 14, 28, and 42 days. Tendon structural integrity will be examined biomechanically at 1, 3, 5, 7, and 9 weeks after tenotomy.
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