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

ABSTRACT: IL-1? is a key mediator of bone resorption in inflammatory settings, such as rheumatoid arthritis (RA). IL-1? 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? also has suppressive properties on osteoclastogenesis in primary human peripheral blood monocytes and RA synovial macrophages. Early addition of IL-1?, prior to or together with RANKL, strongly inhibited human osteoclastogenesis as assessed by generation of TRAP(+) multinucleated cells. IL-1? 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? rendered early-stage human OCPs refractory to RANK stimulation. Similar inhibitory effects of IL-1? were observed using RA synovial macrophages. One mechanism of RANK inhibition was IL-1?-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? 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.

SUBMITTER: Lee B 

PROVIDER: S-EPMC3016227 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature