Multiple roles of M-CSF in human osteoclastogenesis.

Abstract

Although the critical role of M-CSF in osteoclastogenesis is well documented, there has been no detailed analysis of how it regulates human osteoclast formation and function in vitro. We used a human osteoclastogenesis model employing CFU-GM osteoclast precursors cultured for 14 days on dentine with RANKL, with varying exposure to exogenous human M-CSF. Short-term treatment of precursors with M-CSF (10-100 ng/mL) resulted in increased proliferation with or without RANKL. Treatment with M-CSF (1-100 ng/mL) for 14 days caused a biphasic concentration-dependent stimulation of formation, fusion, and resorption peaking at 10-50 ng/mL and almost complete abolition of resorption at 100 ng/mL. Time-course studies using M-CSF (25 ng/mL) showed that osteoclast size, nuclei/cell, and resorption increased with longer duration of M-CSF treatment. When treatment was restricted to the first 4 days, M-CSF (25-100 ng/mL) stimulated formation of normal numbers of osteoclasts that resorbed less. Blockade of endogenous M-CSF signaling with neutralizing M-CSF antibody during the first week of culture extensively inhibited osteoclastogenesis, whereas blockade during the second week produced only a small reduction in resorption. Treatment with M-CSF during the second week of culture caused a small increase in osteoclast number and a concentration-dependent increase in cytoplasmic spreading with inhibition of resorption. We have shown that M-CSF modulates multiple steps of human osteoclastogenesis, including proliferation, differentiation and fusion of precursors. In the later stages of osteoclastogenesis, M-CSF modulates osteoclast-resorbing activity, but is not required for survival. Modulation of M-CSF signaling is a potential therapeutic target for conditions associated with excess bone resorption.

• Authors: Jason M Hodge, Mark A Kirkland, Geoffrey C Nicholson
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 102 Issue 3 Pg. 759-68 (Oct 15 2007) ISSN: 0730-2312 [Print] United States
• PMID: 17516513 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2007 Wiley-Liss, Inc.

Chemical References

• Membrane Glycoproteins
• Macrophage Colony-Stimulating Factor
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Bone Resorption
• Cell Differentiation
• Cell Proliferation
• Cell Survival
• Cells, Cultured
• Cytoplasm (metabolism)
• Fetal Blood (cytology)
• Granulocyte-Macrophage Colony-Stimulating Factor (metabolism)
• Humans
• Macrophage Colony-Stimulating Factor (metabolism, physiology)
• Membrane Glycoproteins (metabolism)
• Models, Biological
• Osteoclasts (cytology, metabolism)
• Signal Transduction
• Time Factors