Herbimycin A, a pp60c-src tyrosine kinase inhibitor, inhibits osteoclastic bone resorption in vitro and hypercalcemia in vivo

Toshiyuki Yoneda, Carolyn Lowe, Chang Ho Lee, Gloria Gutierrez, Maria Niewolna, Paul J. Williams, Elzbieta Izbicka, Yosimasa Uehara, Gregory R. Mundy

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

Since absence of expression of the c-src gene product in mice indicates that the pp60c-src tyrosine kinase is required and essential for osteoclastic bone resorption, we tested the effects of the antibiotic herbimycin A, which is an inhibitor of pp60c-src on osteoclastic bone resorption in vitro and on hypercalcemia in vivo. We examined the effects of herbimycin A on the formation of bone resorbing osteoclasts in mouse long-term marrow cultures, on isolated rodent osteoclasts and on bone 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 determined the effects of herbimycin A ( 100 ng/ml) on src tyrosine kinase activity in mouse marrow cultures and found that it was decreased. Herbimycin A also decreased elevated blood calcium levels that were induced either by repeated subcutaneous injections of recombinant human interleukin-1α or by a human tumor. There was no evidence for toxicity in any of these culture systems or in mice treated with herbimycin A. A different tyrosine kinase inhibitor that does not inhibit pp60c-src was used as a control and caused none of these effects. These data suggest that pp60c-src tyrosine kinase inhibitors may be useful pharmacologic inhibitors of osteoclastic bone resorption and hypercalcemia.

Original languageEnglish (US)
Pages (from-to)2791-2795
Number of pages5
JournalJournal of Clinical Investigation
Volume91
Issue number6
DOIs
StatePublished - Jun 1993
Externally publishedYes

Keywords

  • Bone resorption
  • Hypercalcemia
  • Osteoclast
  • Ppo60
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Medicine(all)

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