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B Signaling during Human Osteoclast Differentiation by Inhibiting TREM-2 Expression1
* Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021;
Division of Rheumatology, College of Medicine, Korea University, Seoul, Korea;
Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021;
Department of Medicine and Microbiology and Immunology, Veterans Affairs Medical Center and University of Oklahoma Health Science Center, Oklahoma City, OK 73104;
¶ Department of Medicine, Veterans Affairs Medical Center, University of California, San Francisco, CA 92357; and
|| Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021
Induction of effective osteoclastogenesis by RANK (receptor activator of NF-
B) requires costimulation by ITAM-coupled receptors. In humans, the TREM-2 (triggering receptor expressed on myeloid cells 2) ITAM-coupled receptor plays a key role in bone remodeling, as patients with TREM-2 mutations exhibit defective osteoclastogenesis and bone lesions. We have identified a new rapidly induced costimulatory pathway for RANK signaling that is dependent on TREM-2 and mediated by calcium signaling. TREM-2-dependent calcium signals are required for RANK-mediated activation of calcium/calmodulin-dependent protein kinase (CaMK)II and downstream MEK and ERK MAPKs that are important for osteoclastogenesis. IL-10 inhibited RANK-induced osteoclastogenesis and selectively inhibited calcium signaling downstream of RANK by inhibiting transcription of TREM-2. Down-regulation of TREM-2 expression resulted in diminished RANKL-induced activation of the CaMK-MEK-ERK pathway and decreased expression of the master regulator of osteoclastogenesis NFATc1. These findings provide a new mechanism of inhibition of human osteoclast differentiation. The results also yield insights into crosstalk between ITAM-coupled receptors and heterologous receptors such as RANK, and they identify a mechanism by which IL-10 can suppress cellular responses to TNFR family members.
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 This work was supported by National Institutes of Health Grants HL073400 (to R.B.S.) DE019420 and AR046713 (to L.B.I.) and a grant from the Arthritis Foundation (to K.-H.P.-M.).
2 Address correspondence and reprint requests to Dr. Lionel B. Ivashkiv, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address: IvashkivL{at}hss.edu
3 Abbreviations used in this paper: pOC, osteoclast precursor; CaMK, calcium/calmodulin-dependent protein kinase; ChIP, chromatin immunoprecipitation; DAP12, DNAX-activating protein of 12 kDa; Mitf, microphthalmia-associated transcription factor; MMP9, matrix metallopeptidase 9; OSCAR, osteoclast-associated receptor; PIR-A, paired Ig-like receptor A; PLC, phospholipase C; RANK, receptor activator of NF-B; RANKL, RANK ligand; RNAi, RNA interference; SIRP, signal regulatory protein; TRAF6, TNF receptor-associated factor 6; TRAP, tartrate-resistant acid phosphatase; TREM-2, triggering receptor expressed on myeloid cells 2.
4 The online version of this article contains supplemental material.
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  J.-D. Ji, K.-H. Park-Min, Z. Shen, R. J. Fajardo, S. R. Goldring, K. P. McHugh, and L. B. Ivashkiv Inhibition of RANK Expression and Osteoclastogenesis by TLRs and IFN-{gamma} in Human Osteoclast Precursors J. Immunol., December 1, 2009; 183(11): 7223 - 7233. [Abstract] [Full Text] [PDF]
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