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    Direct Inhibition of Human RANK+ Osteoclast Precursors Identifies a Homeostatic Function of IL-1{beta}

    J Immunol. 2010 Oct 8. [Epub ahead of print]

    Interleukin 1 (IL-1β) promotes osteoclastogenesis by inducing RANKL expression on stromal cells and synergizing with RANKL to promote late stage osteoclast differentiation. These authors examined the early stage effects of IL-1β on osteoclastogenesis in vitro. They found that IL-1β suppressed osteoclastogenesis in primary human peripheral blood monocytes and RA synovial macrophages. This effect was associated with decreased expression of RANK, the costimulatory molecule, triggering receptor expressed on myeloid cells 2 (TREM2) and the B cell linker adaptor important for transmitting RANK-induced signals. They also found that IL-1β-induced induced proteolytic shedding of the M-CSF receptor c-Fms.
    Authors: Lee B, Kim TH, Jun JB, et. al

    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.

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