SB 242784, a Selective Inhibitor of the Osteoclastic V-H ⁺ -ATPase, Inhibits Arterial Calcification in the Rat

Abstract

Abstract-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 ϩ -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 ϩ -ATPase inhibitor SB 242784, the cytokine osteoprotegerin, and the amino bisphosphonates alendronate and ibandronate. (Circ Res. 2002;91:547-552.)e recently proposed the hypothesis that arterial calcification is linked to bone resorption 1,2 to explain the association between increased bone resorption and increased arterial calcification that has been seen in the vitamin D-treated rat, 1 in the osteoprotegerin-deficient mouse, 3 and in patients with postmenopausal osteoporosis. 4 -12 One prediction of the hypothesis that arterial calcification is linked to bone resorption is that inhibitors of bone resorption should inhibit arterial calcification. 2 In a previous study, we showed that arterial calcification induced by treatment with warfarin and by treatment with high doses of vitamin D is indeed inhibited by two potent inhibitors of bone resorption, the amino bisphosphonates alendronate and ibandronate, at doses of these drugs known to inhibit bone resorption in the rat. 2,13 In a subsequent investigation, we showed that another potent inhibitor of bone resorption, the cytokine osteoprotegerin, also inhibited arterial calcification at subcutaneous doses of osteoprotegerin that have been shown to inhibit bone resorption in the rat. 14 In the present investigation, we have further tested the hypothesis that arterial calcification is linked to bone resorption by determining the effect of a potent inhibitor of bone resorption with an entirely different mode of action, the small molecule SB 242784, on arterial calcification in the rat.SB 242784 inhibits bone ...

Vitamin D, Shedding Light on the Development of Disease in Peripheral Arteries

“…24 There is increasing evidence of a paradoxical association between osteoporosis and vascular calcification. [52][53][54] The mechanisms underlying this association are beginning to be unraveled 42,[55][56][57] and may account for the inverse association between coronary artery calcification and serum levels of 1␣,25(OH) 2 D 3 . 49 Various inhibitors of bone resorption, including biphosphonates (alendronate and ibandronate), osteoprotegrin, and an inhibitor of osteoclastic V-H ϩ -ATPase (SB 242784) have been shown to inhibit calcification of the arterial media in animal models.…”

“…49 Various inhibitors of bone resorption, including biphosphonates (alendronate and ibandronate), osteoprotegrin, and an inhibitor of osteoclastic V-H ϩ -ATPase (SB 242784) have been shown to inhibit calcification of the arterial media in animal models. 55,56,58 Because none of these agents are known to act directly on the arterial smooth muscle cells, it has been proposed that arterial calcification is directly linked to bone resorption in this model. 56 1␣,25(OH) 2 D 3 may, however, act directly on smooth muscle cells or osteoclastlike cells within the arterial wall.…”

“…55,56,58 Because none of these agents are known to act directly on the arterial smooth muscle cells, it has been proposed that arterial calcification is directly linked to bone resorption in this model. 56 1␣,25(OH) 2 D 3 may, however, act directly on smooth muscle cells or osteoclastlike cells within the arterial wall. 59,60 Medial calcification is common in diabetes and end-stage renal failure, both conditions being associated with peripheral arterial disease.…”

Osteoprotegerin Inhibits Vascular Calcification Without Affecting Atherosclerosis in ldlr (−/−) Mice

“…22 However, even in the context of significantly reduced bone resorption in Fc-OPG-treated ldlr (Ϫ/Ϫ) mice, calcium and phosphate levels were in the normal range. Nevertheless, it is possible that minimal but prolonged elevations in serum calcium and/or phosphate may directly or indirectly affect vascular calcification, as suggested by Price et al 22,36 Alternatively, it is possible that ligands for OPG such as RANKL and tumor necrosis factor-␣-related apoptosis-inducing ligand (TRAIL) may play a role in vascular calcification. RANKL, for example, has been shown by Kaden and colleagues 19 to induce alkaline phosphatase activity and calcification in vascular cells, and our present report shows increased RANKL expression associated with atherosclerotic lesions and the progression of vascular disease.…”

Increased Aortic Stiffness: An Unfavorable Cardiorenal Connection

“…Mediators of calcium and bone homeostasis, including osteoprotegerin and various bone morphogenetic and matrix proteins, may play a role in normal arterial function and in the process of calcium deposition in the aortic wall. 10 Alternatively, several of the calcium/bone regulatory hormones, including parathyroid hormone, parathyroid hormone-related peptide, and calcitonin/calcitonin generelated peptide, have direct effects on vascular tone and could affect aortic stiffness measures, such as characteristic impedance, because the latter is highly sensitive to diameter. 6…”