Inflammatory osteolysis, in conditions such as prosthetic implant loosening, reflects accelerated osteoclast (OC) recruitment, by products of inflammation. Thus, discovering the mechanisms by which local inflammation recruits OCs is central to preventing implant osteolysis and other forms of inflammation-induced bone loss. We have shown that tumor necrosis factor-alpha (TNF) is central to the osteoclastogenesis (OCgn) mediating experimental implant osteolysis. Furthermore, TNF directly induces macrophages to assume the OC phenotype, but must do so in the context of at least permissive levels of the essential osteoclastogenic molecule, RANK ligand (RANKL). RANKL is produced, in turn, by marrow stromal cells under the aegis of TNF. While observations, made during the last funding period, establish TNF and RANKL as central to inflammatory osteolysis, how marrow stromal cells, macrophages and T-lymphocytes mediate TNF-induced OCgn, and implant osteolysis, is unknown. Equally enigmatic are the mechanisms by which TNF enhances RANKL expression by marrow stromal cells, and the structural domains of RANKL, interacting with its receptor, RANK, which promote OCgn. We have developed a series of tools to address these issues. First, we have a chimeric mouse model which enables us to assess the roles of stromal cells, macrophages and T-lymphocytes in TNF-induced OCgn. Second our murine particle osteolysis model permits us to ask these questions in the context of implant loosening. Third, we have extensive experience in assessing regulation of osteoclastogenic genes and identifying the functional components of their promoters. Finally, we have solved the crystal structure of RANKL, which positions us to do the same in the context of the RANKL-RANK complex. Thus, we hypothesize that: (1) marrow stromal cells, macrophages and/or T-lymphocytes directly or indirectly mediate TNF-induced OCgn and implant osteolysis; (2) TNF regulates marrow stromal cell RANKL expression by specific molecular events; and (3) specific structural regions of the RANKL-RANK complex mediate OCgn.
Our Specific Aims are therefore to: (1) determine how marrow stromal cells, macrophages and/or T-lymphocytes directly or indirectly mediate TNF- induced OCgn and implant osteolysis; (2) identify the specific molecular events by which TNF regulates marrow stromal cell RANKL expression; and (3) identify the structural regions of the RANKL-RANK complex which mediate OCgn.
| 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 |
| Otero, Karel; Shinohara, Masahiro; Zhao, Haibo et al. (2012) TREM2 and ýý-catenin regulate bone homeostasis by controlling the rate of osteoclastogenesis. J Immunol 188:2612-21 |
Showing the most recent 10 out of 98 publications
