Published online before print August 15, 2002, doi: 10.1161/01.RES.0000033987.22436.50
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Submitted on March 13, 2002
Revised on August 6, 2002
Accepted on August 7, 2002
SB 242784, a Selective Inhibitor of the Osteoclastic V-H+-ATPase, Inhibits Arterial Calcification in the Rat
Paul A. Price *;
From the Department of Biology, University of California, San Diego, La Jolla, Calif.
* To whom correspondence should be addressed. E-mail: pprice{at}ucsd.edu.
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-teleopeptides, 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 (ATVB 21:1610), and the amino bisphosphonates alendronate and ibandronate (ATVB 21:817).
Key words: SB 242784 • V-H+-ATPase • arterial calcification • vitamin D • bone resorption
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