CSF-1, RANKL and OPG regulate osteoclastogenesis during murine tooth eruption.

During tooth eruption, osteoclast-mediated bone resorption predominates in alveolar bone along the occlusal surface rather than in bone basal to the tooth. CSF-1, RANKL and OPG, regulatory molecules essential for osteoclastogenesis, are expressed during eruption. However, it is unclear if these cytokines exhibit an expression pattern that correlates with sites of osteoclastogenesis in vivo. To address this issue, mouse mandibles, isolated from 1 to 14 days postnatal, were analysed for osteoclast activity using tartrate-resistant acid phosphatase (TRAP) staining as well as colony-stimulating factor-1 (CSF-1), receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin (OPG) mRNA expression using in situ hybridisation. Results showed that CSF-1, RANKL and OPG are expressed in a distinct temporal and spatial manner. In the occlusal region, osteoclast activity was maximal at day 5 and correlated with a relative high expression of CSF-1 and RANKL compared to OPG. In basal bone at this time point, osteoclast activity decreased despite persistent CSF-1 expression and was associated with increased expression of OPG compared to RANKL. By day 8, osteoclastogenesis declined and correlated with upregulation of OPG at the occlusal and basal regions, with this effect continuing throughout eruption. These findings suggest that the spatiotemporal pattern and relative abundance of CSF-1, RANKL and OPG during eruption are key determinants of site-specific osteoclast activity in bone surrounding the tooth. Targeting these cytokines to specific regions in alveolar bone may provide a mechanism for regulating osteoclastogenesis in dental disorders associated with altered tooth eruption.

PDGF BB and bFGF stimulate DNA synthesis and upregulate CSF-1 and MCP-1 gene expression in dental follicle cells.

CSF-1 and MCP-1, released by dental follicle cells, stimulate the influx of monocytes into the follicle sac and enhance the formation of osteoclasts that, in turn, resorb alveolar bone for the eruption pathway. PDGF and bFGF, released by cells adjacent to the follicle or by activated monocytes, are prime candidates that may regulate CSF-1 and MCP-1 gene expression. The present study demonstrates that PDGF and bFGF are mitogens for dental follicle cells and stimulate CSF-1 and MCP-1 mRNA, but with different time course kinetics. Peak induction of CSF-1 mRNA was observed at 6-8h, while maximal MCP-1 induction was observed at 2h. These findings suggest that MCP-1 is an early chemotactic signal for monocytes and that subsequent release of CSF-1 may act synergistically with MCP-1 to enhance monocyte influx. Further understanding of the molecular mechanisms by which cytokines regulate CSF-1 and MCP-1 may lead to more effective treatment regimens for disorders associated with abnormal tooth eruption.