Interferons-α and -γ Inhibit Interleukin-1β-Stimulated Osteoclast-Like Cell Formation in Long-Term Human Marrow Cultures

Abstract

Immune cell products can have major effects on bone remodeling. Cytokines, such as interleukin-1 (IL-1), are potent stimulators of bone resorption, whereas interferon-gamma (IFN-gamma) inhibits bone resorption stimulated by these factors. Bone resorption is a result of either increased numbers of osteoclasts, increased activity of individual osteoclasts, or both. Recently, we have shown that human recombinant IFN-gamma is a potent inhibitor of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-induced formation of multinucleated cells (MNC) that express the osteoclast phenotype. However, it is unknown if other IFNs share this capacity to inhibit MNC formation. Therefore, we tested the effects of natural IFNs-alpha and -gamma and Escherichia coli-derived recombinant human IFN-gamma on MNC formation and on granulocyte-macrophage (CFU-GM) colony formation (an early osteoclast precursor) in human marrow cultures treated with IL-1 beta or CSF-GM, respectively, to determine their effects on human osteoclast formation. Each type of IFN inhibited CFU-GM colony formation similarly in a dose-dependent fashion, with 50% inhibition seen at 64-250 U/ml. Natural or recombinant IFN-gamma inhibited IL-1 beta-stimulated MNC formation in a dose-dependent manner with an ID50 of 1-16 U/ml. IFN-alpha was more potent than IFN-gamma, with an ID50 of less than 1 U/ml. Furthermore, both IFN-alpha and -gamma inhibited fusion of precursors of these multinucleated cells. These data demonstrate that IFNs-alpha and -gamma inhibit MNC formation by inhibiting the growth of precursors for these cells as well as their subsequent fusion.