Molecular Mechanisms in Bone Resorption

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DESCRIPTION (provided by applicant): Osteoporosis is a public health problem that affects approximately 25 million people in the United States. Regardless of the etiology, osteoporosis is characterized by an imbalance in bone remodeling, such that osteoclastic bone resorption exceeds osteoblastic bone formation, which leads to low bone mass. The specific timing and localized expression of cherubism indicates that it is a unique and novel model of human osteoclastogenesis, bone resorption and osteopenia. It is also tempting to speculate that the unique physical characteristics of the mouth and alveolar bone can provide a link between osteonecrosis of the jaw and cherubism. For example, in both conditions bone lesions are limited to the jaw despite the entire skeleton being exposed to aminobisphosphonates or expressing the SH3BP2 mutation. We have assessed 17 cherubism probands and have found that all of the SH3BP2 mutations activate nuclear factor of activated T cells (nuclear factor of activated T cells c1 or NFATc1 is the master switch of osteoclastogenesis) and induce expression of tartrate resistant acid phosphatase (TRAP) in the RAW 264.7 pre-osteoclastic cell line. Our recent studies suggest that SH3BP2 stimulates a phosphatidylinositol-specific phospholipase C (PI-PLC), and the production of inositol phosphate 3 (IP3) leads to release of calcium from the endoplasmic reticulum. The increase in intracellular calcium can activate calcineurin, which dephosphorylates NFATc1 and promotes its translocation to the nucleus leading to osteoclastogenesis. Hypothesis: SH3BP2 mutations in cherubism patients alter binding of SH3BP2 to other regulatory or signaling proteins, with at least one result being enhanced NFATc1 activity and consequent osteoclastogenesis. The overall goal of this project is to determine the role of SH3BP2 in regulating osteoclastogenesis. We propose to examine this by looking at mutant and wild-type SH3BP2 phosphorylation (specific aim 1), binding (specific aim 2), and function (specific aim 3). The candidate will use the resources and time made available through the K02 program to visit the laboratories to learn novel techniques in viral infection and osteoclastogenesis, mouse phenotyping, and approaches to genetic analysis of human disease. Moreover he will expand his collaborative efforts with senior basic investigators at Cleveland Clinic and nearby affiliated Case Western Reserve. These investigators will provide examples of how to run a successful lab and provide periodic feedback on the progress of the candidate's research as well as being excellent resources for basic and technical scientific problems and troubleshooting. PUBLIC HEALTH RELEVANCE: New information about mechanisms of bone resorption may facilitate the development of novel strategies to decrease bone resorption and may lead to new treatments for osteoporosis. We propose to use the model of cherubism, a rare disorder characterized by giant cell bone resorptive tumors of the bones of the jaw, to explore novel pathways that regulate bone resorption. K02 funding for this project will help the candidate develop significantly as an independent scientist by protecting his time in the lab.