Osteoclasts express high levels of pp60c-src in association with intracellular membranes.

Abstract

Deletion of the c-src gene in transgenic mice by homologous recombination leads to osteopetrosis, a skeletal defect characterized by markedly deficient bone resorption (Soriano, P., C. Montgomery, R. Geske, and A. Bradley. 1991. Cell. 64:693-702), demonstrating a critical functional role of pp60c-src in osteoclast activity. Since decreased bone resorption could result from a defect either within the osteoclast or within other cells present in its environment, indirectly affecting osteoclast functions, we determined which cell(s) in bone expressed high levels of pp60c-src Measuring pp60c-src protein and kinase activities in osteoclasts and immunolocalizing pp60c-src in bone, we find that expression of pp60c-src is nearly as high in osteoclasts as in brain and platelets. In contrast, other bone cells contain only very low levels of the protein. In addition, expression of the c-src gene product increases when bone marrow cells are induced to express an osteoclast-like phenotype by 1,25-dihydroxy-vitamin D3, further suggesting that high expression of pp60c-src is part of the osteoclast phenotype. Three other src-like kinases, c-fyn, c-yes, and c-lyn, are also expressed in osteoclasts at ratios to pp60c-src similar to what is found in platelets. These src-related proteins do not, however, compensate for the absence of pp60c-src in the src- mice, thereby suggesting that pp60c-src may have a specific function in osteoclasts. Although further work is necessary to elucidate what the critical role of pp60c-src in osteoclasts is, our observation that the protein is associated mostly with the membranes of intracellular organelles suggests the possibility that this role might be at least in part related to the targeting or fusion of membrane vesicles.

U0126 and PD98059, Specific Inhibitors of MEK, Accelerate Differentiation of RAW264.7 Cells into Osteoclast-like Cells

“…1) (21). Cathepsin K (22, 23) and c-Src (24,25), which are known markers of osteoclasts, were also induced in the multinuclear cells. These results showed that the multinuclear TRAP-positive cells from RAW264.7 cells possessed major characteristics of osteoclasts.…”

Wortmannin, a specific inhibitor of phosphatidylinositol‐3 kinase, blocks osteoclastic bone resorption

“…It has been shown that pp60 ....... is required for the ruffled border formation of osteoclasts [16][17][18][19]. Since it is suggested that PI-3 kinase is activated by pp60 ....... [20,21], it is natural to speculate that PI-3 kinase is involved in osteoclastic bone resorption.…”

“…Fax: (81) (3) 3812-0544. in mice induced osteopetrosis, a disease characterized by reduced osteoclastic bone resorption [16]. Indeed, osteoclasts have been reported to express a high level of pp60 ..... [17,18].…”

The many faces of Src: multiple functions of a prototypical tyrosine kinase

“…Although Src is expressed in most cell-types, targeted disruption of Src leads to only one major phenotype ± osteopetrosis or a failure to resorb bone due to an intrinsic defect in osteoclasts Soriano et al, 1991). Osteoclasts express high levels of Src and the lack of this molecule leads to dramatic defects in the ability of this cell-type to resorb bone and organize its actin cytoskeleton (Horne et al, 1992;Lowell et al, 1996;Ne et al, 1996;Schwartzberg et al, 1997). However, the nature of the defect(s) in signal transduction in these cells remains unclear.…”