Transforming Growth Factor-β1 Increases mRNA Levels of Osteoclastogenesis Inhibitory Factor in Osteoblastic/Stromal Cells and Inhibits the Survival of Murine Osteoclast-like Cells

Osteoclastogenesis inhibitory factor (OCIF), also termed osteoprotegerin (OPG), is a secreted member of the tumor necrosis factor (TNF) receptor family. It inhibits bone resorptionin vivoand osteoclast-like cell (OCL) formationin vitro.To better understand the biological role of OCIF, we first examined the effects of various osteotropic agents on OCIF mRNA levels in mouse calvarial osteoblasts. Northern blot analysis showed that stimulators of OCL formation such as 1,25-(OH)2D3, prostaglandin E2(PGE2), parathyroid hormone (PTH), and interleukin 1 (IL-1) decreased OCIF mRNA levels. In contrast, transforming growth factor (TGF)-β1 increased OCIF mRNA levels in primary osteoblasts as well as in osteoblastic/stromal cell lines. Since it was reported that both TGF-β1 and OCIF not only inhibited OCL formation but also impaired the survival of OCL by inducing apoptosisin vitro,we next examined the possible involvement of OCIF in TGF-β1-induced impairment of OCL survival. In a mouse bone marrow culture, we confirmed that addition of OCIF or TGF-β1 decreased the number of surviving OCL. Anti-OCIF IgG, which completely neutralized the effect of OCIF, partially prevented the TGF-β1-induced decrease in the number of OCL. Our results suggest that (i) downregulation of OCIF expression is one of the mechanisms for the stimulatory effects of 1,25(OH)2D3, PGE2, PTH, and IL-1 on osteoclastogenesis; and (ii) the TGF-β1-induced apoptosis of OCL is mediated, at least in part, by upregulation of OCIF expression.