Macrophage Inflammatory Protein-1α Induces Osteoclast Formation by Activation of the MEK/ERK/c-Fos Pathway and Inhibition of the p38MAPK/IRF-3/IFN-β Pathway

Multiple myeloma (MM) is a bone disease that affects many individuals. It was recently reported that macrophage inflammatory protein (MIP)-1 alpha is constitutively secreted by MM cells. MIP-1 alpha causes bone destruction through the formation of osteoclasts (OCs). However, the molecular mechanism underlying MIP-1 alpha-induced OC formation is not well understood. In the present study, we attempted to clarify the mechanism whereby MIP-1 alpha induces OC formation in a mouse macrophage-like cell line comprising C7 cells. We found that MIP-1 alpha augmented OC formation in a concentration-dependent manner; moreover, it inhibited IFN-beta and ISGF3 gamma mRNA expression, and IFN-beta secretion. MIP-1 alpha increased the expressions of phosphorylated ERK1/2 and c-Fos and decreased those of phosphorylated p38MAPK and IRF-3. We found that the MEK1/2 inhibitor U0126 inhibited OC formation by suppressing the MEK/ERK/c-Fos pathway. SB203580 induced OC formation by upregulating c-fos mRNA expression, and SB203580 was found to inhibit IFN-beta and IRF-3 mRNA expressions. The results indicate that MIP-1 alpha induces OC formation by activating and inhibiting the MEK/ERK/c-Fos and p38MAPK/IRF-3 pathways, respectively, and suppressing IFN-beta expression. These findings may be useful in the development of an OC inhibitor that targets intracellular signaling factors. J. Cell. Biochem. 111: 1661-1672, 2010. (C) 2010 Wiley-Liss, Inc.