SB 242784, a selective inhibitor of the osteoclastic V-H+ATPase, inhibits arterial calcification in the rat.
The present experiments were carried out to further test the hypothesis that arterial calcification is linked to bone resorption by determining whether the selective inhibition of bone resorption with SB 242784, a specific inhibitor of the osteoclastic V-H+-ATPase, will inhibit arterial calcification. Treatment for 96 hours with toxic doses of vitamin D caused widespread calcification in the aorta and in the femoral, mesenteric, hepatic, renal, and carotid arteries, and treatment with SB 242784 completely prevented the vitamin D-induced calcification of each of these arteries at a dose of 40 mg/kg per day and significantly reduced calcification at a dose of 10 mg/kg per day. Treatment with vitamin D also caused extensive calcification in the lungs, tracheal cartilage, and kidneys, and treatment with SB 242784 prevented or reduced calcification at each of these sites. Measurement of serum levels of cross-linked N-telopeptides, a specific measure of bone resorption activity, showed that treatment with vitamin D alone produced the expected 2.4-fold increase in bone resorption activity and that concurrent treatment with the 40-mg dose of SB 242784 reduced bone resorption activity to below control levels. With the inclusion of the present results, there are now three types of bone resorption inhibitors (each with an entirely different mode of action on the osteoclast) that share the ability to potently inhibit arterial calcification in the rat, the V-H+-ATPase inhibitor SB 242784, the cytokine osteoprotegerin, and the amino bisphosphonates alendronate and ibandronate.
Price
Paul A
PA
Department of Biology, University of California, San Diego, La Jolla, Calif 92093-0368, USA. pprice@ucsd.edu
June
Helen H
HH
Buckley
Jessica R
JR
Williamson
Matthew K
MK
D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D001862:Bone Resorption / Q000517:prevention & control; D002114:Calcinosis / Q000139:chemically induced / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D010006:Osteoblasts / Q000201:enzymology; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D014807:Vitamin D / Q000633:toxicity
D007211:Indoles; D010880:Piperidines; C118025:SB 242784; D014807:Vitamin D; D025262:Vacuolar Proton-Translocating ATPases