Osteoclast to Osteocyte Crosstalk in Accelerated Bone Turnover

PROJECT SUMMARY/ABSTRACT This proposal comprises a five-year research and career development program for Dr. Diana Athonvarangkul to achieve independence as an investigator in disorders of bone and mineral metabolism. Dr. Athonvarangkul is a physician-scientist who completed her training in an NIH-sponsored Medical Scientist Training Program. The proposed research and career development activities will occur at Yale University. To facilitate her goal of leading her own independent research group, she has developed a training program based on high-yield didactics and professional development opportunities with support from a dedicated mentoring committee comprising scientists with a broad range of expertise relevant to the proposal and an impressive record of mentorship. She has laid out a clear timeline for these activities with timing of subsequent publications and acquisition of funding. The combination of research and career development plans described in this proposal will allow the candidate to mature into a successful and independent physician-scientist. Osteoporosis affects 10 million Americans and leads to 2 million broken bones each year. While a great deal is known about the molecular pathways by which osteoclasts remove bone, relatively little is known about how the most abundant cell type in bone, the osteocyte, remodels bone. Osteocytes remove bone from their surrounding matrix in a process known as osteocytic osteolysis. Our laboratory established that during lactation, osteocytic osteolysis is the physiological response to increased maternal calcium demand. The focus of this proposal is to elucidate mechanisms regulating osteocytic osteolysis using a lactation model, with an emphasis on how the osteoclasts and osteocytes coordinate their resorbing activities. Aim 1 will interrogate whether osteoclastic bone resorption influences a phenotypic switch in which osteocytes upregulate osteoclast-like gene programs and enlarge their lacunae and canalicular network. Aim 2 will follow up on previous observations to determine whether the lactational hormone, parathyroid hormone-related peptide (PTHrP), stimulates production of Receptor Activator of NFB Ligand (RANKL) to activate osteocytic osteolysis. Aim 3 will evaluate whether transforming growth factor beta (TGF) is a coupling factor released by osteoclast activity that regulates osteocytic osteolysis by interacting with PTHrP/PTH1R signaling. Aims 1 and 2 of this proposal will allow Dr. Athonvarangkul to gain experience and proficiency in the approaches needed to study bone biology. Aim 3 will facilitate the discovery of new molecule(s) and communication pathways among bone cells. As an independent investigator, Dr. Athonvarangkul will use the skills acquired in this proposal to determine how communication between osteoclasts and osteocytes is disrupted in diseases with excess bone loss. The experiments presented in this proposal will provide a new mechanistic understanding of intercellular communication within the bone environment during reproduction and may identify new therapeutic targets for the treatment of osteoporosis.