Bone loss in the oral cavity can occur as a result of many local and systemic processes. Among these is periodontal disease, a widespread, chronic condition that afflicts a large portion of the adult U.S. population. This disease process is characterized by a loss of tooth attachment and resorption of alveolar bone. How osteoclasts mediate the resorption process is poorly understood. Even less well understood is the mechanism by which osteoclasts are recruited to the resorption site. One mechanism may be through the local release of chemoattractants. Colony stimulating factor-1 (CSF-1) is an important chemoattractant for osteoclasts. CSF-1 is released by osteoblasts in response to LPS, TNF-a, PTH and a wide variety of other hormones and cytokines. Osteoclasts will migrate up a gradient of CSF-1. Cytokinesis, the process of cell movement, involves prominent cytoskeletal changes. This research group has shown that CSF-1 induces rapid cytoplasmic spreading and actin reorganization in normal osteoclasts, but not in cells obtained from mice with targeted disruption of the src gene, indicating a central role for src in this process. They have also observed differences in the pattern of proteins that are tyrosine phosphorylated in normal vs. src-negative osteoclasts in response to CSF-1. To explore the molecular basis for these differences, proposed experiments have been designed to focus on the acute effects of CSF-1 on actin polymerization, on the role of src in this response and on further characterizing an 85 kDa phosphoprotein (pp85) which is selectively phosphorylated by CSF-1 in wild type, but not src-negative, osteoclasts and which binds Grb2. Other proposed experiments will explore the regulation of the lipid kinase, phosphoinositol 3-kinase (PI3-kinase), by CSF-1 in osteoclasts. Recently it has been shown that activation of PI3-kinase is necessary for CSF-1-induced spreading to occur. Preliminary experiments demonstrated that CSF-1 causes PI3-kinase to associate with c-fms, with a resultant increase in lipid-kinase activity. These changes do not occur in src-negative osteoclasts providing possible mechanistic insight into the pathway by which CSF-1 influences cytokinesis in osteoclasts and the role Src plays in that process. In combination, these studies should help to better define the cellular mechanisms by which CSF-1 influences the motility of mature osteoclasts and lead to more effective strategies for improving dental health.
Showing the most recent 10 out of 21 publications
