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TNF-Induced Osteoclastogenesis and Inflammatory Bone Resorption Are Inhibited by Transcription Factor RBP-J

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TNF-Induced Osteoclastogenesis and Inflammatory Bone Resorption Are Inhibited by Transcription Factor RBP-J Published January 16, 2012 Article TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J Baohong Zhao,1 Shannon N. Grimes,1 Susan Li,1 Xiaoyu Hu,1,2 and Lionel B. Ivashkiv1,2,3 1Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10065 2Department of Medicine, Weill Cornell Medical College, New York, NY 10065 3Graduate Program in Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10065 Downloaded from Tumor necrosis factor (TNF) plays a key role in the pathogenesis of inflammatory bone resorption and associated morbidity in diseases such as rheumatoid arthritis and periodontitis. Mechanisms that regulate the direct osteoclastogenic properties of TNF to limit pathological bone resorption in inflammatory settings are mostly unknown. Here, we show that the transcription factor recombinant recognition sequence binding protein at the J site (RBP-J) strongly suppresses TNF-induced osteoclastogenesis and inflammatory bone resorption, but has minimal effects on physiological bone remodeling. Myeloid-specific deletion of RBP-J jem.rupress.org converted TNF into a potent osteoclastogenic factor that could function independently of receptor activator of NF-B (RANK) signaling. In the absence of RBP-J, TNF effectively induced osteoclastogenesis and bone resorption in RANK-deficient mice. Activation of RBP-J selectively in osteoclast precursors suppressed inflammatory osteoclastogenesis and arthritic bone resorption. Mechanistically, RBP-J suppressed induction of the master regulator of osteoclastogenesis (nuclear factor of activated T cells, cytoplasmic 1) by attenuating c-Fos on December 21, 2014 activation and suppressing induction of B lymphocyte–induced maturation protein-1, thereby preventing the down-regulation of transcriptional repressors such as IRF-8 that block osteoclast differentiation. Thus, RBP-J regulates the balance between activating and repressive signals that regulate osteoclastogenesis. These findings identify RBP-J as a key upstream negative regulator of osteoclastogenesis that restrains excessive bone resorption in inflammatory settings. CORRESPONDENCE The Journal of Experimental Medicine Lionel B. Ivashkiv: TNF is an inflammatory cytokine important and tissue stromal cells to express receptor acti- [email protected] for immunity and inflammation. The resound- vator of NF-B (RANK) ligand (RANKL), ing success of TNF blockade therapy has dem- the key factor that induces differentiation and Abbreviations used: Blimp1, B lymphocyte–induced matura- onstrated a key role for TNF in the pathogenesis function of osteoclasts, which are multinucle- tion protein-1; BMM, of autoimmune/inflammatory diseases such as ated myeloid lineage cells that are capable of BM-derived macrophage; ChIP, rheumatoid arthritis (RA), inflammatory bowel efficient bone resorption. In addition, TNF can chromatin immunoprecipitation; IRF-8, IFN regulatory factor-8; disease, and psoriasis (Locksley et al., 2001; act directly on osteoclast precursors, often in M-CSF, macrophage colony- Sethi et al., 2009; Taylor and Feldmann, 2009). synergy with RANKL, to promote osteoclas- stimulating factor; MNC, multi- In addition to driving chronic inflammation, togenesis (Azuma et al., 2000; Kobayashi et al., nucleated cell; NFATc1, nuclear factor of activated T cells, cyto- TNF has been implicated in pathological bone 2000; Lam et al., 2000; Li et al., 2000; Kim plasmic 1; OPG, osteoprote- resorption (osteolysis) that accompanies inflam- et al., 2005; Boyce et al., 2006; Teitelbaum, gerin; RA, rheumatoid arthritis; matory arthritis and periodontitis and repre- 2006; Yao et al., 2006; Schett and Teitelbaum, RANK, receptor activator sents an important component of morbidity as 2009). Despite activating similar signaling of NF-B; RANKL, RANK ligand; RBP-J, recombinant it contributes to pain, loss of function, and de- recognition sequence binding formity (Boyce et al., 2006; Teitelbaum, 2006; © 2012 Zhao et al. This article is distributed under the terms of an Attribution– protein at the J site; siRNA, Schett and Teitelbaum, 2009). An established Noncommercial–Share Alike–No Mirror Sites license for the first six months after small interfering RNA; the publication date (see http://www.rupress.org/terms). After six months it is mechanism by which TNF promotes inflamma- available under a Creative Commons License (Attribution–Noncommercial–Share TRAP, tartrate-resistant Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/ acid phosphatase. tory bone resorption is activation of osteoblasts by-nc-sa/3.0/). The Rockefeller University Press $30.00 J. Exp. Med. Vol. 209 No. 2 319-334 319 www.jem.org/cgi/doi/10.1084/jem.20111566 Published January 16, 2012 pathways as does RANKL, TNF does not effectively induce mediator of signaling by the canonical Notch pathway osteoclast differentiation in the absence of RANKL; mecha- (Kopan and Ilagan, 2009), where Notch receptor cytoplasmic nisms that regulate the direct osteoclastogenic properties of domains translocate to the nucleus, bind to RBP-J, and induce TNF to limit pathological bone resorption in inflammatory RBP-J transcription-activating function. Accumulating settings are mostly unknown (Yao et al., 2009). evidence shows that RBP-J is also critically involved in other RANKL is a member of the TNF family of cytokines that signaling pathways, such as the Wnt–-catenin (Shimizu et al., acts in concert with macrophage colony-stimulating factor 2008) and NF-B pathways (Plaisance et al., 1997; Izumiya (M-CSF) and co-stimulatory immunoreceptor tyrosine-based et al., 2009), and is also targeted by viral proteins (Hayward, activation motif (ITAM)–associated receptors and integrins 2004; Izumiya et al., 2009) and cellular proteins of unknown to function as the major physiological inducer of osteoclasto- function (Taniguchi et al., 1998; Beres et al., 2006). Thus, genesis. RANKL works by inducing the expression and RBP-J functions as a central transcription factor that receives function of nuclear factor of activated T cells, cytoplasmic 1 inputs from several signaling pathways. RBP-J regulates cell (NFATc1), a transcription factor that serves as a “master reg- differentiation, proliferation, and survival, and plays important ulator” of osteoclastogenesis and activates expression of genes roles in cell fate decisions and diverse cellular functions, such important for osteoclast differentiation, fusion, and bone as stem cell maintenance, neurogenesis, and lymphocyte resorption. The positive signaling pathways used by the development (Maillard et al., 2005; Kopan and Ilagan, 2009). Downloaded from RANKL receptor RANK to activate NFATc1 are well In myeloid lineage cells, RBP-J has been implicated in established and include activation of canonical and nonca- inflammatory macrophage activation (Hu et al., 2008), DC nonical NF-B pathways, mitogen-activated kinase (MAPK) differentiation, and maintenance of CD8 DC populations pathways leading to activation of AP-1 and CREB transcrip- (Caton et al., 2007). Although many of these functions are tion factors, and calcium signaling; effective calcium signaling related to its role in Notch signaling, RBP-J function is context- depends on activation of co-stimulatory ITAM-associated dependent, and under inflammatory conditions RBP-J plays receptors (Takayanagi, 2007; Novack and Teitelbaum, 2008). a key role in expression of immune response genes not related jem.rupress.org More recently, it has become clear that osteoclastogenesis to canonical Notch signaling (Hu et al., 2008). RBPJ allelic is restrained by transcriptional repressors that are constitutively polymorphisms have recently been linked with RA (Stahl expressed in osteoclast precursors and inhibit expression of et al., 2010), but mechanisms by which RBP-J may contribute NFATc1 and osteoclast-related genes (Lee et al., 2006; Hu to RA pathogenesis are not known, and the role of RBP-J in et al., 2007; Kim et al., 2007; Zhao et al., 2009; Miyauchi et al., osteoclastogenesis and inflammatory bone resorption has not 2010; Zhao and Ivashkiv, 2011). RANK signaling needs to been investigated. on December 21, 2014 overcome the barrier imposed by these transcriptional repressors RBP-J modulates signaling by at least two pathways that in order for osteoclastogenesis to proceed. Constitutively have been implicated in osteoclastogenesis: NF-B and the expressed repressors of osteoclastogenesis include Eos, in- Notch pathway, which has been shown to modestly suppress hibitors of differentiation/DNA binding (Ids), v-maf muscu- physiological RANKL-induced osteoclastogenesis (Yamada loaponeurotic fibrosarcoma oncogene family protein B (MafB), et al., 2003; Bai et al., 2008). Thus, we investigated the role IFN regulatory factor-8 (IRF-8), and B cell lymphoma 6 (Bcl6), of RBP-J in osteoclastogenesis and bone resorption. RBP-J and RANKL overcomes inhibition by down-regulating their modestly suppressed RANKL-induced osteoclastogenesis expression and repressive function (Lee et al., 2006; Hu et al., in vitro and had no discernable effect on physiological bone 2007; Kim et al., 2007 Zhao et al., 2009; Miyauchi et al., remodeling in vivo. In striking contrast, myeloid-specific dele- 2010; Zhao and Ivashkiv, 2011). One mechanism by which tion of RBP-J resulted in dramatically increased TNF-induced RANK signaling down-regulates MafB, IRF-8, and Bcl6 ex- osteoclastogenesis, comparable
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