Colony-Stimulating Factor-1 Stimulates the Fusion Process in Osteoclasts

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Abstract
Colony-stimulating factor-1 (CSF-1), also called macrophage colony-stimulating factor, is required for growth, differentiation, activation, and survival of cells of the mononuclear phagocytic system. This cytokine has been shown to be essential for osteoclast development as well as for inducing both proliferation and differentiation of osteoclast progenitors. It also sustains survival of mature osteoclasts and stimulates spreading and migration of these cells. In the present in vitro study, the formation of large tartrate-resistant acid phosphatase (TRAP)-positive cells with a high number of nuclei was observed when osteoclasts isolated from rat long bones were incubated with CSF-1. These large cells, cultured on plastic, bind calcitonin and form F-actin along the edges of the cells. Fusion to such large TRAP-positive multinucleated cells in the presence of CSF-1 and the formation of pits were also observed on dentine slices. Quantitative data obtained from cultures on plastic demonstrated that the number of osteoclasts slightly increased in the course of 72 h in the presence of 250 pM CSF-1, whereas it decreased rapidly after 24 h in the absence of CSF-1, which confirms that this cytokine is required for the survival of osteoclasts. The number of nuclei per osteoclast was maximal after 16 h of incubation with CSF-1, namely twice the value found in the absence of CSF-1. The maximal effect of the cytokine on the fusion process was observed at a concentration of 250 pM. A calculation of the medians of the average frequency of nuclei distribution per osteoclast resulted in four nuclei per osteoclast in the absence and six in the presence of CSF-1. Genistein and herbimycin A, inhibitors of tyrosine kinases, inhibited the fusion induced by CSF-1. The data suggest that CSF-1 induces osteoclast fusion and that tyrosine kinase(s) are involved in this process. The fusion process may continue throughout the entire life of an osteoclast.