Osteoprotegerin Inhibits Artery Calcification Induced by Warfarin and by Vitamin D

Abstract

Abstract-The present experiments were carried out to test the hypothesis that arterial calcification is linked to bone resorption by determining whether the selective inhibition of bone resorption with osteoprotegerin will inhibit arterial calcification. In the first test, arterial calcification was induced by treating 22-day-old male rats with warfarin, a procedure that inhibits the ␥-carboxylation of matrix Gla protein and causes extensive calcification of the arterial media.Compared with rats treated for 1 week with warfarin alone, rats treated with warfarin plus osteoprotegerin at a dose of 1 mg/kg per day had dramatically reduced alizarin red staining for calcification in the aorta and in the carotid, hepatic, mesenteric, renal, and femoral arteries, and they had 90% lower levels of calcium and phosphate in the abdominal aorta (PϽ0.001) and in tracheal ring cartilage (PϽ0.01). More rapid arterial calcification was induced by treating 49-day-old male rats with toxic doses of vitamin D. Treatment for 96 hours with vitamin D caused widespread alizarin red staining for calcification in the aorta and the femoral, mesenteric, hepatic, renal, and carotid arteries, and osteoprotegerin completely prevented calcification in each of these arteries and reduced the levels of calcium and phosphate in the abdominal aorta to control levels (PϽ0.001). Treatment with vitamin D also caused extensive calcification in the lungs, trachea, kidneys, stomach, and small intestine, and treatment with osteoprotegerin reduced or prevented calcification in each of these sites. Measurement of serum levels of cross-linked N-teleopeptides showed that osteoprotegerin dramatically reduced bone resorption activity in each of these experiments (PϽ0.001). Therefore, we conclude that doses of osteoprotegerin that inhibit bone resorption are able to potently inhibit the calcification of arteries that is induced by warfarin treatment and by vitamin D treatment. 1,2 to explain the association between the 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 previous studies, we have shown that arterial calcification induced by treatment with warfarin and by treatment with high doses of vitamin D is indeed inhibited by 2 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 the present investigations, we have determined the effect of another potent inhibitor of bone resorption, osteoprotegerin, on arterial calcification by using subcutaneous doses of this protein that have been shown to inhibit bone resorption in the rat.Osteoprotegerin is a secreted protein of the tumor necrosis factor family, which regulat...

Serum osteoprotegerin concentrations are decreased in women with the polycystic ovary syndrome

“…In conceptual agreement with a role of decreased OPG levels in the development of cardiovascular disease, animal models showed an accelerated progression of atherosclerotic lesions with calcification in mice lacking OPG (33), OPG knockout mice display arterial calcification (34), and parenteral administration of OPG in rats prevents the vascular calcification induced by treatment with warfarin and supraphysiological doses of vitamin D (35).…”

Vascular Calcification Mechanisms

“…Indeed, cells derived from the vascular media undergo bone-and cartilage-like phenotypic change and calcification in vitro under various conditions, and is discussed in further detail below (36 -40). Third, bone turnover leading to release of circulating nucleational complexes has been proposed to explain the link between vascular calcification and osteoporosis in postmenopausal women (41)(42)(43). Fourth, cell death can provide phospholipidrich membranous debris and apoptotic bodies that may serve to nucleate apatite, especially in diseases where necrosis and apoptosis are prevalent, such as atherosclerosis (34,44,45).…”

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

“…(15) Agents that enhance bone quality also reduce cardiovascular calcification. (16)(17)(18)(19)(20)(21)(22)(23) Additionally, soft-tissue calcification including vascular calcification is a common feature of genetic mouse and rat models harboring defects associated with bone mineralization. (24)(25)(26) Clinical improvements in bone health, regardless of the initial bone defect, ameliorate progression of cardiovascular disease.…”