Herbimycin A, a pp60c-src tyrosine kinase inhibitor, inhibits osteoclastic bone resorption in vitro and hypercalcemia in vivo.
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-1 alpha 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.
Yoneda
T
T
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7877.
Lowe
C
C
Lee
C H
CH
Gutierrez
G
G
Niewolna
M
M
Williams
P J
PJ
Izbicka
E
E
Uehara
Y
Y
Mundy
G R
GR
D000818:Animals; D016227:Benzoquinones; D001853:Bone Marrow; D001862:Bone Resorption / Q000188:drug therapy*; D001842:Bone and Bones / Q000187:drug effects; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D006934:Hypercalcemia / Q000097:blood / Q000188:drug therapy*; D047029:Lactams, Macrocyclic; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011809:Quinones / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017828:Rifabutin / Q000031:analogs & derivatives; D019061:src-Family Kinases
D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D011809:Quinones; D017828:Rifabutin; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human