RAMP Involvement in PTH Regulation of Bone Metabolism

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DESCRIPTION (provided by applicant): The goal of this proposed study is to provide the Principal Investigator, Jeanne M. Nervina, DMD, PhD, with the opportunity to develop as an independent researcher to complement her clinical training in orthodontics. Her training will be conducted under the guidance of the project's sponsors, Dr, Sotirios Tetradis and Dr. Harvey Herschman. Dr. Nervina's career goal is to pursue an academic career and establish herself as an independent dentist scientist conducting molecular biology research, mentoring students at all levels, and practicing orthodontics. Bone quality and quantity are important indicators of orofacial pathology and are predictors of outcome success for many dental surgical procedures. Uncoupled activity of bone forming osteoblasts and bone resorbing osteoclasts produce significant changes in bone metabolism. Our rationale is that understanding the molecular mechanisms of bone metabolism will greatly impact medicine and dentistry. Parathyroid hormone (PTH) has significant anabolic effects on bone, yet we do not understand the molecular mediators of these effects. We have identified receptor activity modifying protein 3 (RAMP3) as a PTH-induced primary gene in mouse osteoblasts. In preliminary studies we found that PTH also regulates RAMP1, but not RAMP2, mRNA levels in mouse osteoblasts. RAMP1, 2, and 3 are critical coactivators of calcitonin and calcitonin receptor-like receptors. Ligands for these receptors have significant anabolic effects on bone. We hypothesize that RAMP proteins participate in PTH's anabolic effect on osteoblasts. To test our hypothesis we propose three Specific Aims. (1) We will characterize PTH-induced RAMP1 and RAMP3 gene expression in mouse osteoblasts in vitro and in vivo. (2) Adenoviruses expressing RAMP1 and RAMP3 will be generated to assess the role of these genes in regulating osteoblast phenotype. (3) RAMP1 and RAMP3 transgenic mice will be generated using the COL1A1 promoter to target transgene expression to osteoblasts. Each mouse line will be studied for changes in bone phenotype at the gross, cellular, and molecular levels. These studies will help us understand the mechanisms of PTH-induced RAMP1 and RAMP3 gene expression and they will unveil the impact of these genes on osteoblast function.