Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice.

Abstract

Targeted disruption of the c-src proto-oncogene in mice has shown that src expression is required for normal bone resorption, since the src-deficient mutants develop osteopetrosis. To evaluate the mechanisms by which src-deficiency affects osteoclast function, we treated src-deficient mice with the stimulants of bone resorption, IL-1, parathyroid hormone, and parathyroid hormone-related protein, and analyzed the effects by quantitative bone histomorphometry and electron microscopy. Increased numbers of multinucleated cells with the morphological characteristics of osteoclasts appeared on bone surfaces, but these cells did not form ruffled borders or normal resorption lacunae. To confirm these in vivo findings, we cultured src-mutant bone marrow cells on dentine slices in the presence of 1,25 dihydroxyvitamin D3. Increased numbers of multinucleated cells were formed, but unlike normal murine bone marrow cells, they did not form resorption pits. These results indicate that osteoclasts appear in the absence of pp6Or, but that pp6O C expression is required for mature osteoclasts to form ruffled borders and resorb bone. (J. Clin. Invest. 1992.

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

“…(34) c-Src is also known to play an important role in OC activity in vivo, as demonstrated by c-Src -/-mice, which are severely osteopetrotic owing to an absence of OC activity. (35)(36)(37)(38) While the precise mechanism(s) remain(s) to be elucidated, data shown here (Fig. 1) and previously (7,8) suggest that dasatinib inhibits in vitro osteoclastogenesis at concentrations at which cfms but not c-Src is affected.…”

Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation

“…Numerous multinucleated TRAP-positive cells are present in the c-src mutant mice but these cells do not form ruffled borders and resorption lacunae [34][35]. In the present study, TRAPpositive cells were detected in ossicle sections treated with ZA alone and PTH and ZA.…”

Molecular Understanding of Osteoclast Differentiation and Physiology

“…αVβ3 integrin, an adhesion receptor binding the Arg-GlyAsp (RGD) motifs of matrix proteins, is essential for normal osteoclast function since mice lacking beta3 integrins fail to spread or form sealing zones, thus becoming osteosclerotic [7]. Similarly, mice deficient in src, a ubiquitously expressed non-receptor tyrosine kinase display osteopetrosis characterized by dysfunctional osteoclasts with abnormal sealing zones and αVβ3 localization [8,9].…”