Bone is a dynamic tissue undergoing a constant remodeling process through out life. During remodeling, osteoclasts resorb bone and osteoblasts form new bone. Abnormal bone remodeling, secondary to increased osteoclast maturation or activation, contributes to bone destruction in inflammatory arthritis and osteoporosis. Discerning immunomodulatory signals that govern osteoclast development, function, or survival is essential to understanding both normal as well as pathological bone processes. Towards this end my research focuses on the molecular mechanisms that lead to osteoclast differentiation and activation.
In particular my lab is focusing on the role of the signaling adapter protein DAP12 and its associated receptors in osteoclast development and function. DAP12 is a transmembrane protein found in myeloid cells, has a short extracellular domain, and transmits activation signals upon ligation of associated receptors. Our studies to date reveal that DAP12 signaling is required for normal in vitro osteoclast development and that mice genetically deficient in DAP12 have increased bone mass secondary to decreased activity of osteoclasts. Additionally, mice deficient in DAP12 and FcR?, another ITAM (immunoreceptor tyrosine-based activation motif) containing adapter protein, are severely osteopetrotic secondary to abnormal osteoclast development and function. We subsequently showed that Syk tyrosine kinase mediates the ITAM activation signals in osteoclasts. Ongoing studies continue to focus on the roles of DAP12 and several DAP12-associated receptors during in vitro and in vivo osteoclast activation. Additionally we are investigating the role inhibitory immunoreceptors in osteoclast regulation.
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Selected Publications
M.B. Humphrey, M. R. Daws, S. C. Spusta, E. C. Niemi, J. A. Torchia, L. L. Lanier, W. E. Seaman, and M. C. Nakamura. (2005) TREM2, a DAP12-associated Receptor, Regulates Osteoclast Differentiation and Function. Journal of Bone and Mineral Research, published on line October 24, 2005 doi 10.1359/JBMR.051016.
N. E. Lane, W. Yao, M. C. Nakamura, M. B. Humphrey , D. Kimmel, X. Huang, D. Sheppard, P.F. Ross, and S. L. Teitelbaum. (2004) Mice lacking Integrin b5 Subunit Have Accelerated Osteoclast Maturation and Increased Activity in the Estrogen Deficient State. Journal of Bone and Mineral Research, published on line October 25, 2004 doi 10.1359/JBMR041017.
Attila Mócsai*, Mary Beth Humphrey*, Jessica A.G. Van Ziffle, Yongmei Hu, Andrew Burghardt, Steven Spusta, Sharmila Majumdar, Lewis L. Lanier, Clifford A. Lowell, Mary C. Nakamura. (2004) The Immunomodulatory Adapter Proteins DAP12 and FcR? Regulate Development of Functional Osteoclasts Through the Syk Tyrosine Kinase. Proceedings of the National Academy of Sciences, 101:6158-6163. (* Co-first authors)
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