Direct Inhibition of Human RANK(+) Osteoclast Precursors Identifies a Homeostatic Function of IL-1 beta
- Authors
- Lee, Bitnara; Kim, Tae-Hwan; Jun, Jae-Bum; Yoo, Dae-Hyun; Woo, Jin-Hyun; Choi, Sung Jae; Lee, Young Ho; Song, Gwan Gyu; Sohn, Jeongwon; Park-Min, Kyung-Hyun; Ivashkiv, Lionel B.; Ji, Jong Dae
- Issue Date
- 15-11월-2010
- Publisher
- AMER ASSOC IMMUNOLOGISTS
- Citation
- JOURNAL OF IMMUNOLOGY, v.185, no.10, pp.5926 - 5934
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF IMMUNOLOGY
- Volume
- 185
- Number
- 10
- Start Page
- 5926
- End Page
- 5934
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/115326
- DOI
- 10.4049/jimmunol.1001591
- ISSN
- 0022-1767
- Abstract
- IL-1 beta is a key mediator of bone resorption in inflammatory settings, such as rheumatoid arthritis (RA). IL-1 beta 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-1 beta also has suppressive properties on osteoclastogenesis in primary human peripheral blood monocytes and RA synovial macrophages. Early addition of IL-1 beta, prior to or together with RANKL, strongly inhibited human osteoclastogenesis as assessed by generation of TRAP(+) multinucleated cells. IL-1 beta 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-1 beta rendered early-stage human OCPs refractory to RANK stimulation. Similar inhibitory effects of IL-1 beta were observed using RA synovial macrophages. One mechanism of RANK inhibition was IL-1 beta-induced proteolytic shedding of the M-CSF receptor c-Fms that is required for RANK expression. These results identify a homeostatic function of IL-1 beta in suppressing early OCPs that contrasts with its well-established role in promoting later stages of 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.
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Collections - College of Medicine > Department of Medical Science > 1. Journal Articles
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