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* National Research Laboratory for Regulation of Bone Metabolism and Disease, Medical Research Center for Gene Regulation, Brain Korea 21, Chonnam National University Medical School, Gwangju, Korea; and
Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan
IL-1 is a potent cytokine that can induce bone erosion in inflammatory sites such as rheumatoid joint regions via activation of osteoclasts. Not only is IL-1 capable of activating osteoclasts, but it is also a key cytokine involved in the differentiation, multinucleation, and survival of osteoclasts. Herein, we show that IL-1 has the potential to drive osteoclast differentiation via a receptor activator of NF-
B ligand (RANKL)/RANK-independent mechanism. Although IL-1 has a synergistic effect on RANKL-induced osteoclast formation, IL-1 alone cannot induce osteoclast differentiation from osteoclast precursors (bone marrow-derived macrophages (BMMs)) due to a lack of IL-1 signaling potential in these cells. However, we demonstrate that overexpression of the IL-1RI receptor in BMMs or induction of IL-1RI by c-Fos overexpression enables IL-1 alone to induce the formation of authentic osteoclasts by a RANKL/RANK-independent mechanism. The expression of IL-1RI is up-regulated by RANKL via c-Fos and NFATc1. Furthermore, the addition of IL-1 to IL-1RI overexpressing BMMs (IL-1/IL-1RI) strongly activates NF-B, JNK, p38, and ERK which is a hallmark gene activation profile of osteoclastogenesis. Interestingly, IL-1/IL-1RI does not induce expression of c-Fos or NFATc1 during osteoclast differentiation, although basal levels of c-Fos and NFATc1 seem to be required. Rather, IL-1/IL-1RI strongly activates MITF, which subsequently induces osteoclast-specific genes such as osteoclast-associated receptor and tartrate-resistant acid phosphatase. Together, these results reveal that IL-1 has the potential to induce osteoclast differentiation via activation of microphthalmia transcription factor under specific microenvironmental conditions.
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1 This work is supported in part by the Korea Science and Engineering Foundation (KOSEF) National Research Laboratory (NRL) Program Grant funded by the Korean government (MEST) (R0A-2007–000-20025–0); Grant R13–2002-013–03001–0 from the Korea Science and Engineering foundation through the Medical Research Center for Gene Regulation at Chonnam National University; the Korea Health 21 R&D Project (A060164) from Ministry of Health and Welfare. J.H.K. and K.K. were supported by the Brain Korea 21 Project.
2 Address correspondence and reprint requests to Dr. Nacksung Kim, Department of Pharmacology, Chonnam National University Medical School, Hak-Dong 5, Dong-Ku, Gwangju, Korea. E-mail address: nacksung{at}chonnam.ac.kr
3 Abbreviations used in this paper used in this paper: M-CSF, macrophage colony-stimulating factor; RANKL, receptor activator of NF B ligand; MITF, microphthalmia transcription factor; NFAT, NF of activated T cell; TRAF, TNF receptor-associated factor; IL-R, IL-1 receptor; BMM, bone marrow-derived macrophages; TRAP, tartrate-resistant acid phosphatase; OSCAR, osteoclast-associated receptor; ChIP, chromatin immunoprecipitation; ERK, extracellular signal-related kinase; EMSA, electrophoretic mobility shift assay.
4 The online version of this article contains supplemental material.
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