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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE012459-02
Application #
2837988
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1997-12-01
Project End
2000-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Zhu, Meiling; Sun, Ben-Hua; Saar, Katarzyna et al. (2016) Deletion of Rac in Mature Osteoclasts Causes Osteopetrosis, an Age-Dependent Change in Osteoclast Number, and a Reduced Number of Osteoblasts In Vivo. J Bone Miner Res 31:864-73
Yao, Chen; Yao, Gang-Qing; Sun, Ben-Hua et al. (2014) The transcription factor T-box 3 regulates colony-stimulating factor 1-dependent Jun dimerization protein 2 expression and plays an important role in osteoclastogenesis. J Biol Chem 289:6775-90
Kawano, Tsutomu; Zhu, Meiling; Troiano, Nancy et al. (2013) LIM kinase 1 deficient mice have reduced bone mass. Bone 52:70-82
Yao, Gang-Qing; Wu, Jian-Jun; Troiano, Nancy et al. (2012) Selective deletion of the membrane-bound colony stimulating factor 1 isoform leads to high bone mass but does not protect against estrogen-deficiency bone loss. J Bone Miner Metab 30:408-18
Itokowa, Takashi; Zhu, Mei-ling; Troiano, Nancy et al. (2011) Osteoclasts lacking Rac2 have defective chemotaxis and resorptive activity. Calcif Tissue Int 88:75-86
Yao, Gang-Qing; Wu, Jian-Jun; Troiano, Nancy et al. (2011) Targeted overexpression of Dkk1 in osteoblasts reduces bone mass but does not impair the anabolic response to intermittent PTH treatment in mice. J Bone Miner Metab 29:141-8
Kukreja, Anjli; Radfar, Soroosh; Sun, Ben-Hua et al. (2009) Dominant role of CD47-thrombospondin-1 interactions in myeloma-induced fusion of human dendritic cells: implications for bone disease. Blood 114:3413-21
Williams, Bart O; Insogna, Karl L (2009) Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone. J Bone Miner Res 24:171-8
Yao, Gang-Qing; Wu, Jian-Jun; Ovadia, Shira et al. (2009) Targeted overexpression of the two colony-stimulating factor-1 isoforms in osteoblasts differentially affects bone loss in ovariectomized mice. Am J Physiol Endocrinol Metab 296:E714-20
Yu, Kuan-ping; Itokawa, Takashi; Zhu, Mei-ling et al. (2007) Breast cancer-associated gene 3 (BCA3) is a novel Rac1-interacting protein. J Bone Miner Res 22:628-37

Showing the most recent 10 out of 21 publications