HERBIMYCIN-A, A PP60(C-SRC) TYROSINE KINASE INHIBITOR, INHIBITS OSTEOCLASTIC BONE-RESORPTION INVITRO AND HYPERCALCEMIA INVIVO

Since absence of expression of the c-src gene product in mice indicate s that the pp60c-src tyrosine kinase is required and essential for ost eoclastic bone resorption, we tested the effects of the antibiotic her bimycin A, which is an inhibitor of pp60c-src on osteoclastic bone res orption in vitro and on hypercalcemia in vivo. We examined the effects of herbimycin A on the formation of bone resorbing osteoclasts in mou se long-term marrow cultures, on isolated rodent osteoclasts and on bo ne resorption in organ cultures of fetal rat long bones stimulated by parathyroid hormone. We found that herbimycin A in concentrations of 1 -100 ng/ml inhibited bone resorption in each of these systems. We dete rmined the effects of herbimycin A (100 ng/ml) on src tyrosine kinase activity in mouse marrow cultures and found that it was decreased. Her bimycin A also decreased elevated blood calcium levels that were induc ed either by repeated subcutaneous injections of recombinant human int erleukin-1alpha or by a human tumor. There was no evidence for toxicit y in any of these culture systems or in mice treated with herbimycin A . A different tyrosine kinase inhibitor that does not inhibit pp60c-sr c was used as a control and caused none of these effects. These data s uggest that pp60c-src tyrosine kinase inhibitors may be useful pharmac ologic inhibitors of osteoclastic bone resorption and hypercalcemia.