Osteoclasts are the exclusive cells responsible for bone resorption. Governing their number and function can reduce bone mineral loss during ageing, and therefore treat osteoporosis and other bone degenerative diseases that affect a significant number of Americans. The long-term goal of this proposal is to elucidate the function of protein tyrosine phosphatases (PTP), specifically PTP Shp2, in osteoclastogenesis and bone remodeling. Taking a tissue/cell specific gene knockout approach, I bred Shp2 floxed allele with LysM-Cre and Ctsk-Cre transgenic lines respectively to generate mice lacking Shp2 expression specifically in osteoclast precursors and mature osteoclasts. My preliminary data demonstrate that mice lacking Shp2 in osteoclasts are osteopetrotic, and bone marrow cells from the mutant mice have impaired osteoclastogenesis ex vivo, implicating a critical role for Shp2 in osteoclast development, bone remodeling and mineral maintenance. With these unique mouse models and their cellular derivatives, I will be in an unique position to address three important questions: Aim 1: to determine how Shp2 supports the survival of osteoclast precursors and their proliferation and differentiation towards functional osteoclasts;Aim 2: to determine whether the osteopetrotic phenotype in osteoclast-specific Shp2 deficient mice is caused by reduction of osteoclast numbers, and/or function;Aim 3: to define how is the signaling evoked by macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor kB ligand (RANKL) regulated by Shp2 for osteoclastogenesis and osteoclast bone resorptive function. Understanding this molecular machinery in detail will provide insights into designing new therapeutics for ageing related bone degenerative diseases for which there are no restorative or regenerative treatment. PUBLIC HEALTH RELEVANCE: We will study the role of protein tyrosine phosphatase Shp2 in osteoclastogenesis and osteoclast functional activation. Our research will lead to a better understanding of the moceluar and cellular mechanism of Shp2 in osteoclast development and functional regulation, and identifying potential novel targets for treating osteoporosis and other bone degenerative diseases.