Synovial cells from a patient with rheumatoid arthritis produce osteoclastogenesis inhibitory factor/osteoprotegerin: reciprocal regulation of the production by inflammatory cytokines and basic fibroblast growth factor

Abstract.

To understand the involvement of osteoclastogenesis inhibitory factor (OCIF), also called osteoprotegerin (OPG), in the pathogenesis of bone destruction in rheumatoid arthritis (RA), we investigated the cytokine network involved in the production of OCIF by human fibroblast-like synovial (HFLS) cells from a patient with RA. Inflammatory cytokines, such as interleukin (IL)-1β, IL-6 plus soluble IL-6 receptor (sIL-6R), IL-17, and tumor necrosis factor (TNF)-α, which are elevated in synovial fluid in RA, upregulated the production of OCIF to a level (5–20 ng/ml) sufficient to inhibit osteoclastogenesis in vitro. These inflammatory cytokines (except for IL-6 plus sIL-6R) stimulate OCIF production directly or indirectly through stimulation of prostaglandin E₂ (PGE₂) synthesis. In contrast to the findings with inflammatory cytokines, basic fibroblast growth factor (bFGF) inhibited the production of OCIF by the cells in a dose-dependent manner. While bFGF enhanced both the inflammatory cytokine-mediated release of PGE₂ and the PGE₂-mediated OCIF production, it significantly suppressed OCIF production by negating the direct stimulatory effect of the inflammatory cytokines. These findings suggest that bFGF in the synovial fluid of patients with RA may lead to severe joint destruction by suppressing the production of OCIF by HFLS cells.