Osteoporosis always reflects enhanced osteoclastic relative to osteoblastic activity and hence, the long term goals of this project have been elucidation of the cellular mechanisms of bone resorption. Significant progress has been made in the last five years reflecting, in particular, the development of models whereby highly enriched populations of osteoclasts can be studied in vitro. Using such models, we have shown that bone resorption is a multistep process initiated by osteoclast-matrix recognition and attachment. In fact, it is now clear that the capacity of the cell to degrade bone ultimately depends upon its matrix binding ability. Recent evidence implicates integrins as the major class of molecules mediating cell-matrix recognition and attachment and we and others have shown that such is the case as regards the osteoclast. In particular, the integrin alphav/beta3 whose expression, we find, is regulated by the osteoclastogenic hormone, 1,25-dihydroxyvitamin D3, appears to be the major modulator of osteoclast-bone binding and bone resorption. It is also now evident that integrins, in addition to their attachment functions, are capable of initiating intracellular signalling when interacting with specific matrix proteins or peptides. As evidenced by our preliminary data, such is true as regards the osteoclast. Thus, our efforts will be aimed at studying the biology of integrins in the osteoclast as well as determining mechanisms whereby their function in vivo modulates osteoclast recruitment and bone resorption. We therefore specifically propose to: 1) investigate the mechanisms by which 1,25-dihydroxyvitamin d3 regulates integrin expression during osteoclastogenesis, 2) explore the relationship between bone matrix recognition by osteoclasts and delivery of a collagenolytic enzyme to the resorptive microenvironment; and 3) determine if regulation of integrin function modulates osteoclast recruitment and resorptive activity in vivo.
| Izawa, Takashi; Rohatgi, Nidhi; Fukunaga, Tomohiro et al. (2015) ASXL2 Regulates Glucose, Lipid, and Skeletal Homeostasis. Cell Rep 11:1625-37 |
| Warren, Julia T; Zou, Wei; Decker, Corinne E et al. (2015) Correlating RANK ligand/RANK binding kinetics with osteoclast formation and function. J Cell Biochem 116:2476-83 |
| Zou, Wei; Teitelbaum, Steven L (2015) Absence of Dap12 and the ?v?3 integrin causes severe osteopetrosis. J Cell Biol 208:125-36 |
| Fukunaga, Tomohiro; Zou, Wei; Rohatgi, Nidhi et al. (2015) An insulin-sensitizing thiazolidinedione, which minimally activates PPAR?, does not cause bone loss. J Bone Miner Res 30:481-8 |
| Warren, Julia T; Nelson, Christopher A; Decker, Corinne E et al. (2014) Manipulation of receptor oligomerization as a strategy to inhibit signaling by TNF superfamily members. Sci Signal 7:ra80 |
| Fukunaga, Tomohiro; Zou, Wei; Warren, Julia T et al. (2014) Vinculin regulates osteoclast function. J Biol Chem 289:13554-64 |
| Zhu, Tingting; Chappel, Jean C; Hsu, Fong-Fu et al. (2013) Type I phosphotidylinosotol 4-phosphate 5-kinase ? regulates osteoclasts in a bifunctional manner. J Biol Chem 288:5268-77 |
| Zou, Wei; Croke, Monica; Fukunaga, Tomohiro et al. (2013) Zap70 inhibits Syk-mediated osteoclast function. J Cell Biochem 114:1871-8 |
| Zou, Wei; Izawa, Takashi; Zhu, Tingting et al. (2013) Talin1 and Rap1 are critical for osteoclast function. Mol Cell Biol 33:830-44 |
| Deselm, Carl J; Zou, Wei; Teitelbaum, Steven L (2012) Halofuginone prevents estrogen-deficient osteoporosis in mice. J Cell Biochem 113:3086-92 |
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