Diseases of bone loss are a major health issue. Despite the wide availability of anti-resorptive drugs, there is a major need for anabolic agents that increase bone formation in patients to treat a variety of clinical pathologies. We have recently shown that Inhibin A, a peptide hormone normally produced by the gonad, increases bone volume and strength in the intact adult murine skeleton, and protects against gonadectomy-induced bone loss. These effects appear to be mediated by a mechanism that increases bone formation, since no changes in osteoclast numbers or systemic markers of bone resorption are observed. This led us to hypothesize that InhA is also anabolic in other models of bone formation, such as distraction osteogenesis (DO), in which InhA effects on osteoblast proliferation and function might be more pronounced. DO is a unique clinical method of bone formation and is considered a variant of fracture healing that stretches the biological repair process to its natural limits. To test our hypothesis, we enlisted the collaboration of our colleague, Dr. James Aronson, an expert in clinical DO and basic studies of DO in rodent models. We believe the cellular organization and isolation of osteoblastogenesis offered by the DO process makes it a uniquely suitable model to gain insight into the mechanistic basis of Inhibin's stimulatory effects on bone formation. Two Aims are proposed to test the hypothesis. Aim 1 will determine if Inhibin A treatment enhances bone formation and stiffness during distraction osteogenesis, using our transgenic model of InhA overexpression in which we have demonstrated bone anabolic effects. MicroCT, radiography and histomorphometry will be used to quantify total and compartment-specific contributions of InhA to the bone formation response. Tensile mechanical testing will be performed to determine stiffness of new bone formed. Aim 2 will determine the cellular and molecular events mediating Inhibin A enhancement of bone formation during the distraction process. Our focus will be to determine if the mechanisms by which InhA increase bone formation are through increasing cell number in the different zones of regenerating tissue and/or increasing the activity of cells in the osteoblastic lineage that are recruited into the process. The resulting data will demonstrate the anabolic action of Inhibin A during DO, and provide insight into the mechanism(s) that may be targeted for future anabolic therapy development to improve fracture healing. Incomplete or delayed fracture healing is major health issue, particularly in the elderly population, and very few treatments are available. We recently showed that treatment of adult mice with the gonadal hormone Inhibin increases bone mass and strength, suggesting it might also enhance bone formation during fracture healing. Our goal is to determine if Inhibin can increase new bone formation during a model of fracture healing known as limb-lengthening or distraction osteogenesis. If Inhibin can increase the amount of bone made during limb- lengthening, it may also have potential development as a therapy for increasing bone formation during fracture healing.

R21DK074024

2007-07-01

2010-06-30