IL-6 mediates the effects of IL-1 or TNF, but not PTHrP or 1,25(OH) sub(2)D sub(3), on osteoclast-like cell formation in normal human bone marrow cultures

• Published in: Journal of bone and mineral research Vol. 13; no. 3; pp. 393 - 399
• Main Authors: Devlin, R D, Reddy, S V, Savino, R, Ciliberto, G, Roodman, G D
• Format: Journal Article
• Language: English
• Published: 01.03.1998
• ISSN: 0884-0431

A potent interleukin-6 (IL-6) antagonist (Sant 5), which binds tightly to the IL-6 alpha receptor but has impaired gp130 heterodimerization, has been developed recently by site-directed mutagenesis of human IL-6. We report here that Sant 5 inhibits IL-6-stimulated osteoclast-like multinucleated cell (MNC) formation in human marrow cultures but also inhibits the stimulatory effects of IL-1 or tumor necrosis factor alpha (TNF- alpha in these cultures. We further show that a neutralizing antibody to IL-6 also inhibits the stimulatory effects of IL-1 or TNF- alpha in these cultures. In contrast, Sant 5 had no effect on parathyroid hormone related protein (PTHrP) or 1,25-dihydroxyvitamin D sub(3) stimulated MNC formation in human marrow cultures. Transfection of a human marrow stromal cell line, which normally induces osteoclast formation through production of IL-6, with the Sant 5 cDNA driven by a cytomegalovirus (CMV) promoter blocked the capacity of these cells to stimulate osteoclast-like cell formation. These Sant 5 transfected cells and conditioned media from these cells also inhibited the stimulatory effects of the parent cell line on MNC formation. These data suggest that IL-6 mediates the effects of IL-1 and TNF on human osteoclast formation, but in contrast to murine systems, does not mediate the effects of PTHrP. These data further demonstrate that stromal cells transfected with the Sant 5 cDNA can constitutively produce high levels of the IL-6 antagonist and inhibit osteoclast formation in vitro.