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)-1α is constitutively secreted by MM cells. MIP-1α causes bone destruction through the formation of osteoclasts (OCs). However, the molecular mechanism underlying MIP-1α-induced OC formation is not well understood. In the present study, we attempted to clarify the mechanism whereby MIP-1α induces OC formation in a mouse macrophage-like cell line comprising C7 cells. We found that MIP-1α augmented OC formation in a concentration-dependent manner; moreover, it inhibited IFN-β and ISGF3γ mRNA expression, and IFN-β secretion. MIP-1α 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-β and IRF-3 mRNA expressions. The results indicate that MIP-1α induces OC formation by activating and inhibiting the MEK/ERK/c-Fos and p38MAPK/IRF-3 pathways, respectively, and suppressing IFN-β expression. These findings may be useful in the development of an OC inhibitor that targets intracellular signaling factors.
Division of Pharmacotherapy, Kinki University School of Pharmacy, Higashi-Osaka, Osaka, Japan.
Masanobu
M
Tsubaki
Chisato
C
Kato
Ai
A
Isono
Junichi
J
Kaneko
Misako
M
Isozaki
Takao
T
Satou
Tatsuki
T
Itoh
Yasuhiro
Y
Kidera
Yoshihiro
Y
Tanimori
Masashi
M
Yanae
Shozo
S
Nishida
D000818:Animals; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D054405:Chemokine CCL3 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D002070:Butadienes; D054405:Chemokine CCL3; D004791:Enzyme Inhibitors; D007093:Imidazoles; D050838:Interferon Regulatory Factor-3; D009570:Nitriles; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; C113580:U 0126; D016899:Interferon-beta; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580