Direct Inhibition of Human RANK(+) Osteoclast Precursors Identifies a Homeostatic Function of IL-1 betaopen access
- 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
- Nov-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://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/173548
- 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.
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