COLONY-STIMULATING FACTOR-I INDUCES CYTOSKELETAL REORGANIZATION AND C-SRC-DEPENDENT TYROSINE PHOSPHORYLATION OF SELECTED CELLULAR PROTEINS IN RODENT OSTEOCLASTS

Colony-stimulating factor-1 (CSF-1) stimulates motility and cytoplasmi c spreading in mature osteoclasts, Therefore, we examined the cellular events and intracellular signaling pathways that accompany CSF-1-indu ced spreading in normal osteoclasts, To explore the role c-src plays i n these processes, we also studied osteoclasts prepared from animals w ith targeted disruption of the src gene.In normal osteoclasts, CSF-1 t reatment induces rapid cytoplasmic spreading, with redistribution of F -actin from a well-delineated central attachment ring to the periphery of the cell, CSF-1 increases membrane phosphotyrosine staining in ost eoclasts and induces the phosphorylation of several cellular proteins in cultured, osteoclast-like cells, including c-fms, c-src, and an 85- kD Grb2-binding protein, Src kinase activity is increased threefold af ter CSF-1 treatment. In src(-) cells, no attachment ring is present, a nd CSF-1 fails to induce spreading or a change in the pattern of F-act in distribution, Although c-fms becomes phosphorylated after CSF-1 tre atment, the 85-kD protein is significantly less phosphorylated in src- osteoclast-like cells. These results indicate that c-src is critical f or the normal cytoskeletal architecture of the osteoclast, and, in its absence, the spreading response induced by CSF-1 is abrogated, and do wnstream signaling from c-fms is altered.