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J. Biol. Chem., Vol. 283, Issue 17, 11535-11540, April 25, 2008

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Interleukin-6 Directly Inhibits Osteoclast Differentiation by Suppressing Receptor Activator of NF-B Signaling Pathways^*

Fumio Yoshitake¹, Shousaku Itoh¹², Hiroko Narita, Katsuhiko Ishihara, and Shigeyuki Ebisu

From the Department of Restorative Dentistry and Endodontology, Osaka University Graduate School of Dentistry, 1-8, Yamada-oka Suita, Osaka, 565-0871 and the Department of Immunology and Molecular Genetics, Kawasaki Medical School, Kurashiki, Okayama, Japan

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-B 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-B, 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 IB 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.

Received for publication, August 21, 2006 , and in revised form, February 20, 2008.

^* This work was supported by Grants-in-aid for Scientific Research (18592086 and 17659596) from the Japan Society for the Promotion of Science and the 21st Century Center of Excellence titled "Origination of Frontier Bio-Dentistry" at Osaka University Graduate School of Dentistry, which is supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Tel.: 81-6-6879-2927; Fax: 81-6-6879-2927; E-mail: ito{at}dent.osaka-u.ac.jp.

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