Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-kappaB signaling pathways.
Interleukin-6 (IL-6) is a multifunctional cytokine produced by various cells to regulate hematopoiesis, inflammation, immune responses, and bone homeostasis. IL-6 is also known to modulate the differentiation of osteoblasts and osteoclasts. IL-6 is believed to play a positive regulatory role in osteoclast differentiation by inducing the expression of receptor activator of NF-kappaB ligand (RANKL) on the surface of osteoblasts: RANKL then interacts with RANK expressed on osteoclast progenitors, inducing osteoclast differentiation via the RANK signaling pathway, which involves NF-kappaB, JNK, and p38. In this report, we demonstrate that IL-6 can also directly act on osteoclast progenitors to suppress their differentiation via an inhibition of RANK signaling pathways. IL-6 specifically suppressed RANK-mediated IkappaB degradation and JNK activation. Microarray analysis revealed that costimulation with IL-6 and RANKL up-regulates the transcription of MKP1 and MKP7, which encode enzymes that dephosphorylate JNK, and down-regulates the transcription of Senp2 and Cul4A, which are related to the ubiquitin pathway. Thus, IL-6 directly acts on osteoclast progenitors and suppresses their differentiation by regulating the transcription of specific genes related to MAPK phosphatases and the ubiquitin pathway.
Yoshitake
Fumio
F
Department of Restorative Dentistry and Endodontology, Osaka University Graduate School of Dentistry, 1-8, Yamada-oka Suita, Osaka, 565-0871 Japan.
Itoh
Shousaku
S
Narita
Hiroko
H
Ishihara
Katsuhiko
K
Ebisu
Shigeyuki
S
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D054637:Dual-Specificity Phosphatases / Q000378:metabolism; D005786:Gene Expression Regulation; D015850:Interleukin-6 / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology*; D010766:Phosphorylation; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D015850:Interleukin-6; D016328:NF-kappa B; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054638:Dual Specificity Phosphatase 1; D054637:Dual-Specificity Phosphatases; C517020:Dusp1 protein, mouse; C438002:Dusp16 protein, mouse