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Β Homeostatic Function of IL-1 Osteoclast Precursors Identifies a + Direct Inhibition of Human RANK+ Osteoclast Precursors Identifies a Homeostatic Function of IL-1β This information is current as Bitnara Lee, Tae-Hwan Kim, Jae-Bum Jun, Dae-Hyun Yoo, of October 2, 2021. Jin-Hyun Woo, Sung Jae Choi, Young Ho Lee, Gwan Gyu Song, Jeongwon Sohn, Kyung-Hyun Park-Min, Lionel B. Ivashkiv and Jong Dae Ji J Immunol 2010; 185:5926-5934; Prepublished online 8 October 2010; doi: 10.4049/jimmunol.1001591 Downloaded from http://www.jimmunol.org/content/185/10/5926 Supplementary http://www.jimmunol.org/content/suppl/2010/10/08/jimmunol.100159 http://www.jimmunol.org/ Material 1.DC1 References This article cites 47 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/185/10/5926.full#ref-list-1 Why The JI? Submit online. by guest on October 2, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Direct Inhibition of Human RANK+ Osteoclast Precursors Identifies a Homeostatic Function of IL-1b Bitnara Lee,*,1 Tae-Hwan Kim,*,1 Jae-Bum Jun,* Dae-Hyun Yoo,* Jin-Hyun Woo,† Sung Jae Choi,† Young Ho Lee,† Gwan Gyu Song,† Jeongwon Sohn,‡ Kyung-Hyun Park-Min,x Lionel B. Ivashkiv,x and Jong Dae Ji† IL-1b is a key mediator of bone resorption in inflammatory settings, such as rheumatoid arthritis (RA). IL-1b promotes osteoclastogenesis by inducing RANKL expression on stromal cells and synergizing with RANKL to promote later stages of osteoclast differentiation. Because IL-1Rs share a cytosolic Toll–IL-1R domain and common intracellular signaling molecules with TLRs that can directly inhibit early steps of human osteoclast differentiation, we tested whether IL-1b also has suppressive properties on osteoclastogenesis in primary human peripheral blood monocytes and RA synovial macrophages. Early addition of b + IL-1 , prior to or together with RANKL, strongly inhibited human osteoclastogenesis as assessed by generation of TRAP Downloaded from multinucleated cells. IL-1b acted directly on human osteoclast precursors (OCPs) to strongly suppress expression of RANK, of the costimulatory triggering receptor expressed on myeloid cells 2 receptor, and of the B cell linker adaptor important for transmitting RANK-induced signals. Thus, IL-1b rendered early-stage human OCPs refractory to RANK stimulation. Similar inhibitory effects of IL-1b were observed using RA synovial macrophages. One mechanism of RANK inhibition was IL-1b– induced proteolytic shedding of the M-CSF receptor c-Fms that is required for RANK expression. These results identify a ho- meostatic function of IL-1b in suppressing early OCPs that contrasts with its well-established role in promoting later stages of http://www.jimmunol.org/ osteoclast differentiation. Thus, the rate of IL-1–driven bone destruction in inflammatory diseases, such as RA, can be restrained by its direct inhibitory effects on early OCPs to limit the extent of inflammatory osteolysis. The Journal of Immunology, 2010, 185: 5926–5934. one resorption and osteolysis are a prominent feature and of osteoclasts and acts as a potent stimulator of RANK expression a cause of substantial morbidity in several inflammatory (6). RANKL binds to RANK on the cell surface of osteoclast B diseases, including rheumatoid arthritis (RA), perio- precursors (OCPs) and induces the full differentiation of osteo- dontitis, and peri-prosthetic loosening (1–3). Osteoclasts are the clasts and their bone resorbing activity. Osteoprotegerin is another by guest on October 2, 2021 primary bone-resorbing cells and are essential for bone destruction receptor for RANKL and a potent inhibitor of osteoclastogenesis in these inflammatory diseases. Osteoclasts are multinucleated that acts as a decoy receptor for RANKL. Other inflammatory giant cells that are differentiated from hematopoietic cells of molecules also positively or negatively contribute to bone de- myeloid lineage. RANKL and M-CSF are essential molecules for struction by regulating the differentiation of osteoclasts. There- differentiation of osteoclasts from their precursors, and these fore, the extent of bone destruction is determined by the balance osteoclastogenic molecules are abundantly expressed in inflam- between stimulatory and inhibitory factors of osteoclastogenesis matory conditions, such as RA and periodontitis (4, 5). M-CSF in inflammatory conditions. binds to the surface receptor c-Fms (also termed colony-stimulating In RA, several inflammatory molecules, such as TNF-a, IL-1b, factor 1 receptor), which is responsible for early differentiation IL-6, IL-17, and PGs play a vital role in osteoclastogenesis and bone resorption. These molecules promote osteoclastogenesis in- *Hospital for Rheumatic Diseases, Hanyang University; †Division of Rheumatology directly by increasing expression of RANKL and M-CSF by stro- and ‡Department of Biochemistry, College of Medicine, Korea University, Seoul, x mal cells and T cells, and also by acting directly on OCPs to South Korea; and Arthritis and Tissue Degeneration Program, Hospital for Special synergize with RANKL in driving osteoclastogenesis (1, 2). Surgery, New York, NY 10021 Among these molecules, TNF-a is the most important osteoclas- 1B.L. and T.-H.K. contributed equally to this work. togenic molecule in pathologic conditions, such as RA. TNF-a Received for publication May 14, 2010. Accepted for publication September 8, 2010. increases osteoclastogenesis through several different mechanisms This work was supported by Grant A084224 from the Korea Healthcare Technology (7). TNF-a increases the pool size of marrow OCPs, enhances the R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (to J.D.J.) and by grants from the National Institutes of Health (to L.B.I.) and the RANKL-induced osteoclastogenic actions, and increases expres- Arthritis Foundation (to K.-H.P.-M.). sion of RANKL in synovial cells, T cells, and osteoblast/stromal Address correspondence and reprint requests to Dr. Jong Dae Ji, Division of Rheu- cells. matology, College of Medicine, Korea University, 126-1, Anam-Dong 5-Ga, IL-1 is a multifunctional cytokine that has predominately pro- Sungbuk-Ku, Seoul 136-705, South Korea. E-mail address: [email protected] inflammatory properties but can also engage feedback inhibitory The online version of this article contains supplemental material. mechanisms (e.g., induction of glucocorticoid production) that Abbreviations used in this paper: BLNK, B cell linker; COX-2, cyclooxygenase-2; IL-1Ra, IL-1R antagonist; MMP, matrix metalloproteinase; OCP, osteoclast precur- restrain and balance its proinflammatory function (8). This cyto- sor; Pam3Cys, Pam3CysSer(Lys)4; PKC, protein kinase C; RA, rheumatoid arthritis; kine was initially described as an osteoclast-activating factor due TRAP, tartrate-resistant acid phosphatase; TREM-2, triggering receptor expressed on to its potent bone-resorbing activity (9). Like TNF-a, IL-1b also myeloid cells 2. plays an essential role in the pathogenesis of bone destruction in Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 RA. Although IL-1 alone does not induce osteoclastogenesis, it www.jimmunol.org/cgi/doi/10.4049/jimmunol.1001591 The Journal of Immunology 5927 augments RANKL-induced osteoclast differentiation and pro- possibility that IL-1b also may regulate osteoclast differentiation by motes osteoclast activation and survival (10). IL-1 also mediates acting directly on OCPs, similarly to TLR ligands. Because little is TNF-induced bone resorption (11). The IL-1 gene family has known about the direct effect on human osteoclastogenesis by IL-1b, several members, such as IL-1a, IL-1b, and the IL-1R antagonist we examined the effects of IL-1b on osteoclastogenesis in primary (IL-1Ra) (8). IL-1a and IL-1b are agonists, and IL-1Ra is a spe- human peripheral blood monocytes and RA synovial macrophages. cific receptor antagonist. There are two members of the IL-1R We found that IL-1b induces shedding and thereby inactivation of gene family. The type I receptor IL-1RI transduces signals, c-Fms that drives RANK expression and makes early human OCPs whereas IL-1RII does not transduce signals and instead works as refractory to RANK stimulation by downregulating expression of a decoy receptor. IL-1 exerts its biological effects by forming a RANK, its costimulatory receptor, triggering receptor expressed on complex with the IL-1RI and IL-1R accessory protein. IL-1 uses myeloid cells 2 (TREM-2), and downstream signaling molecules, the adaptor molecule MyD88 to activate signaling pathways such as B cell linker (BLNK). These findings identify a homeostatic leading to the activation of NF-kB and MAPKs and downstream function for a predominately inflammatory cytokine and suggest transcription factors that drive inflammatory
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