Titles

Professor, Medicine

Research Interests

Skeletal mass is the product of the activities of two cell types: osteoclasts which resorb bone and osteoblasts which synthesize it. The focus of our laboratory is to delineate the means by which osteoclasts and osteoblasts differentiate and function at the cellular and molecular levels and use this information to understand the pathogenesis of osteoporosis. The projects ongoing in our laboratory include:

1. The role of αv-associated integrins in osteoclastic bone resorption. We find the integrin αvβ3 essential to the resorptive process. We have cloned the α3 integrin cDNAs, and its promoter and have detailed the relevant regulatory mechanisms. This effort has permitted us to pharmacologically prevent osteoporosis by αvβ3 antagonists and generate a β3 knockout mouse with as striking bone phenotype. Using this mouse, we have identified the components of the β3 integrin cytoplasmic domain which regulate osteoclast function and have defined the intracellular signals transmitted by the integrin which activate the cell.
2. The role of TNF in osteoclast regulation. We have shown TNF is a potent bone resorptive agent responsible for inflammatory osteolysis exerting its effect via the p55 TNF receptor. These studies involve various strains of knockout mice lacking TNF isoforms or specific receptors. We also find, using a novel chimeric mouse generated in our laboratory, that TNF-induced osteoclast formation reflects direct targeting of the cytokine to osteoclast precursors, an event requiring constitutive levels of RANK ligand, a TNF family member essential for osteoclast development. Our present studies focus on the interplay of inflammatory cytokines in the pathogenesis of the bone loss of rheumatoid arthritis.

Selected Publications

Assistant