Regulation of osteoclast differentiation and function by the CaMK-CREB pathway

Kojiro Sato^1, 11, Ayako Suematsu^1, 11, Tomoki Nakashima¹, Sayaka Takemoto-Kimura², Kazuhiro Aoki³, Yasuyuki Morishita⁴, Hiroshi Asahara⁵, Keiichi Ohya³, Akira Yamaguchi⁶, Toshiyuki Takai⁷, Tatsuhiko Kodama⁸, Talal A Chatila⁹, Haruhiko Bito^2, 10 & Hiroshi Takayanagi^1, 10

¹  Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University; and Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan.

²  Department of Neurochemistry, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.

³  Department of Hard Tissue Engineering, Section of Pharmacology, Graduate School, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan.

⁴  Department of Human Pathology, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.

⁵  Department of Innovative Surgery, National Center for Child Health and Development, Okura 2-10-1, Setagaya-ku, Tokyo 157-8535, Japan.

⁶  Department of Oral Pathology, Graduate School, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan.

⁷  Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo 4-1, Aoba-ku, Sendai 980-8575, Japan.

⁸  Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan.

⁹  Division of Immunology, Allergy and Rheumatology, Department of Pediatrics, David Geffen School of Medicine at the University of California at Los Angeles, MDCC 12-430, 10833 Le Conte Avenue, Los Angeles, California 90095-1752, USA.

¹⁰  Solution Oriented Research for Science and Technology (SORST), Japan Science and Technology Agency (JST), Honcho 4-1-8, Kawaguchi, Saitama 332-0012, Japan.

¹¹  These authors contributed equally to this work.

Calcium (Ca²⁺) signaling is essential for a variety of cellular responses and higher biological functions. Ca²⁺/calmodulin-dependent kinases (CaMKs) and the phosphatase calcineurin activate distinct downstream pathways that are mediated by the transcription factors cAMP response element (CRE)-binding protein (CREB) and nuclear factor of activated T cells (NFAT), respectively¹. The importance of the calcineurin-NFAT pathway in bone metabolism has been demonstrated in osteoclasts, osteoblasts and chondrocytes^{2, 3, 4, 5}. However, the contribution of the CaMK-CREB pathway is poorly understood, partly because of the difficulty of dissecting the functions of homologous family members^{6, 7, 8}. Here we show that the CaMKIV-CREB pathway is crucial for osteoclast differentiation and function. Pharmacological inhibition of CaMKs as well as the genetic ablation of Camk4 reduced CREB phosphorylation and downregulated the expression of c-Fos, which is required for the induction of NFATc1 (the master transcription factor for osteoclastogenesis^{2, 3}) that is activated by receptor activator of NF-B ligand (RANKL). Furthermore, CREB together with NFATc1 induced the expression of specific genes expressed by differentiated osteoclasts. Thus, the CaMK-CREB pathway biphasically functions to regulate the transcriptional program of osteoclastic bone resorption, by not only enhancing induction of NFATc1 but also facilitating NFATc1-dependent gene regulation once its expression is induced. This provides a molecular basis for a new therapeutic strategy for bone diseases.

	Top