Direct inhibition of human RANK + osteoclast precursors identifies a homeostatic function of IL-1β

Bitnara Lee, Tae Hwan Kim, Jae Bum Jun, Dae Hyun Yoo, Jin Hyun Woo, Sungjae Choi, Young Ho Lee, Gwan Gyu Song, Jeongwon Sohn, Kyung Hyun Park-Min, Lionel B. Ivashkiv, Jong Dae Ji

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

IL-1β is a key mediator of bone resorption in inflammatory settings, such as rheumatoid arthritis (RA). IL-1β 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-1β also has suppressive properties on osteoclastogenesis in primary human peripheral blood monocytes and RA synovial macrophages. Early addition of IL-1β, prior to or together with RANKL, strongly inhibited human osteoclastogenesis as assessed by generation of TRAP + multinucleated cells. IL-1β 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-1β rendered early-stage human OCPs refractory to RANK stimulation. Similar inhibitory effects of IL-1β were observed using RA synovial macrophages. One mechanism of RANK inhibition was IL-1β-induced proteolytic shedding of the M-CSF receptor c-Fms that is required for RANK expression. These results identify a homeostatic function of IL-1β 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.

Original languageEnglish
Pages (from-to)5926-5934
Number of pages9
JournalJournal of Immunology
Volume185
Issue number10
DOIs
Publication statusPublished - 2010 Nov 15

ASJC Scopus subject areas

  • Immunology

Fingerprint Dive into the research topics of 'Direct inhibition of human RANK <sup>+</sup> osteoclast precursors identifies a homeostatic function of IL-1β'. Together they form a unique fingerprint.

  • Cite this