Osteoporosis affects 10 million Americans, and associated fragility fractures cause significant morbidity and mortality. While a great deal is known about the molecular pathways controlling osteoblast and osteoclast function, relatively little is known about the most abundant cell type in bone, the osteocyte. Osteocytes produce sclerostin, a potent inhibitor of bone formation by osteoblasts and an osteoporosis drug target. Notably, the only existing osteoporosis therapy that boosts bone formation, parathyroid hormone (PTH) 1-34 (teriparatide), works in part by reducing sclerostin production by osteocytes. The focus of this grant proposal is to elucidate the intracellular mechanisms controlling osteocyte biology, with an emphasis on sclerostin gene regulation and its control by PTH. Class IIa HDACs (Hdac5 and Hdac4) have been identified as important regulators of osteocytic sclerostin production and osteocyte differentiation in general.
Aim 1 will fully characterize the effects of class IIa HDAC deficiency on osteocyte biology in vivo using multiple independent and complementary approaches.
Aim 2 will interrogate the role of class IIa HDACs in PTH-mediated sclerostin suppression in vivo. Importantly, though some information is known about how class IIa HDACs might control sclerostin expression, much remains unknown. Therefore, Aim 3 will determine novel class IIa HDAC binding proteins and substrates in osteocytes using cutting-edge proteomic approaches. The candidate Dr. Wein is a physician/scientist dedicated to a career in basic investigation in skeletal biology. His education (combined MD/PhD degrees) provides him rigorous training in basic science and human physiology. An endocrinologist subspecializing in metabolic bone diseases, considerable and complementary overlap exists between his clinical and research interests. Beyond the research proposed within, Dr. Wein's career development plan will allow him to maximize the resources within the MGH Endocrine Unit, Harvard Medical School, and the Broad Institute to achieve his career goals. He has identified a mentor, Dr. Henry Kronenberg, who is a worldwide leader in skeletal biology and PTH actions. Dr. Wein and Kronenberg have a plan for frequent meetings to discuss data and career development. Dr. Kronenberg has clearly identified aspects of the research proposed by Dr. Wein which will form the basis of his independent career. Collaborators within the MGH Endocrine Unit and at the Broad institute have been identified, and an advisory committee has been formed to evaluate progress and plan future directions. Dr. Wein will frequently present his data and attend seminars and journal clubs in the MGH Endocrine Division and at the Broad Institute, and will present his findings at international meetings on an annual basis. Formal coursework is planned in grant writing, public speaking, and computational biology to further enhance his probability of success as an independent physician/scientist. Dr. Wein's immediate career goals include acquiring the skills described in this grant proposal in conjunction with his mentor Dr. Kronenberg and collaborators identified within, and publishing first authors manuscripts in order to gain name recognition and to establish himself in the osteocyte field. Dr. Wein's long-term career goal is to establish himself as an independent investigator studying basic cell biology mechanisms controlling bone cell function in vivo. His PhD work with Dr. Laurie Glimcher focused on osteoblast biology, but at this point he needs additional training in skeletal biology and studying osteocytes in vivo and in vitro. Substantial expertise in these areas is present within MGH Endocrine Unit, a collaborative group dedicated to mineral ion metabolism and bone biology, with close attention to relevance to the understanding and treatment of human disease.
Aims 1 and 2 of this grant proposal will allow Dr. Wein to gain experience and expertise in the in vivo approaches required to study osteocyte biology.
Aim 3 will facilitate the discovery of new genes important for osteocyte function: as an independent investigator, Dr. Wein will then use the skills acquired in this grant proposal to determine the phenotype of novel mutant strains.

Public Health Relevance

This study focuses on how osteocytes, the most abundant cell type in bone, function to control bone mass. A complete understanding of osteocyte biology will improve our knowledge of how a drug used to treat osteoporosis (teriparatide) works to build new bone. With the knowledge gained from this study, we ultimately may be able to improve the efficacy of this drug, and design new agents to treat osteoporosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR067285-04
Application #
9464356
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Nicks, Kristy
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
Wein, Marc N; Foretz, Marc; Fisher, David E et al. (2018) Salt-Inducible Kinases: Physiology, Regulation by cAMP, and Therapeutic Potential. Trends Endocrinol Metab 29:723-735
Greenblatt, Matthew B; Tsai, Joy N; Wein, Marc N (2017) Bone Turnover Markers in the Diagnosis and Monitoring of Metabolic Bone Disease. Clin Chem 63:464-474
Tokarz, Danielle; Cisek, Richard; Wein, Marc N et al. (2017) Intravital imaging of osteocytes in mouse calvaria using third harmonic generation microscopy. PLoS One 12:e0186846
He, Qing; Bouley, Richard; Liu, Zun et al. (2017) Large G protein ?-subunit XL?s limits clathrin-mediated endocytosis and regulates tissue iron levels in vivo. Proc Natl Acad Sci U S A 114:E9559-E9568
Kim, Sang Wan; Lu, Yanhui; Williams, Elizabeth A et al. (2017) Sclerostin Antibody Administration Converts Bone Lining Cells Into Active Osteoblasts. J Bone Miner Res 32:892-901
Fulzele, Keertik; Lai, Forest; Dedic, Christopher et al. (2017) Osteocyte-Secreted Wnt Signaling Inhibitor Sclerostin Contributes to Beige Adipogenesis in Peripheral Fat Depots. J Bone Miner Res 32:373-384
Wein, Marc N; Liang, Yanke; Goransson, Olga et al. (2016) SIKs control osteocyte responses to parathyroid hormone. Nat Commun 7:13176
Eda, Homare; Santo, Loredana; Wein, Marc N et al. (2016) Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease. J Bone Miner Res 31:1225-34