Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1610-1616
doi: 10.1161/hq1001.097102
doi: 10.1161/hq1001.097102
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2001 American Heart Association, Inc.
Vascular Biology |
Osteoprotegerin Inhibits Artery Calcification Induced by Warfarin and by Vitamin D
From the Division of Biology, University of California, San Diego, La Jolla.
Correspondence to Dr Paul A. Price, Department of Biology, 0368, University of California, San Diego, La Jolla, CA 92093-0368. E-mail pprice{at}ucsd.edu
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 (P<0.001) and in tracheal ring cartilage (P<0.01). 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 (P<0.001). 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 (P<0.001). 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. These results support the hypothesis that arterial calcification is linked to bone resorption.
Key Words: osteoprotegerin • artery calcification • vitamin D • bone resorption • matrix Gla protein
This article has been cited by other articles:
 |
|
 |
|
  M. Morena, A.-M. Dupuy, I. Jaussent, H. Vernhet, G. Gahide, K. Klouche, A.-S. Bargnoux, C. Delcourt, B. Canaud, and J.-P. Cristol A cut-off value of plasma osteoprotegerin level may predict the presence of coronary artery calcifications in chronic kidney disease patients Nephrol. Dial. Transplant., November 1, 2009; 24(11): 3389 - 3397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Talmor-Barkan, G. Rashid, I. Weintal, J. Green, J. Bernheim, and S. Benchetrit Low extracellular Ca2+: a mediator of endothelial inflammation Nephrol. Dial. Transplant., November 1, 2009; 24(11): 3306 - 3312. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Lewiecki Denosumab in postmenopausal osteoporosis: what the clinician needs to know Therapeutic Advances in Musculoskeletal Diseases, October 1, 2009; 1(1): 13 - 26. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Helas, C. Goettsch, M. Schoppet, U. Zeitz, U. Hempel, H. Morawietz, P. J. Kostenuik, R. G. Erben, and L. C. Hofbauer Inhibition of Receptor Activator of NF-{kappa}B Ligand by Denosumab Attenuates Vascular Calcium Deposition in Mice Am. J. Pathol., August 1, 2009; 175(2): 473 - 478. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Jorgensen, B. Vind, M. Nybo, L. M. Rasmussen, and K. Hojlund Acute hyperinsulinemia decreases plasma osteoprotegerin with diminished effect in type 2 diabetes and obesity Eur. J. Endocrinol., July 1, 2009; 161(1): 95 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Lopez, F. J. Mendoza, F. Guerrero, Y. Almaden, C. Henley, E. Aguilera-Tejero, and M. Rodriguez The calcimimetic AMG 641 accelerates regression of extraosseous calcification in uremic rats Am J Physiol Renal Physiol, June 1, 2009; 296(6): F1376 - F1385. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Panizo, A. Cardus, M. Encinas, E. Parisi, P. Valcheva, S. Lopez-Ongil, B. Coll, E. Fernandez, and J. M. Valdivielso RANKL Increases Vascular Smooth Muscle Cell Calcification Through a RANK-BMP4-Dependent Pathway Circ. Res., May 8, 2009; 104(9): 1041 - 1048. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Akat, M Borggrefe, and J J Kaden Aortic valve calcification: basic science to clinical practice Heart, April 1, 2009; 95(8): 616 - 623. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Rashid, E. Plotkin, O. Klein, J. Green, J. Bernheim, and S. Benchetrit Parathyroid hormone decreases endothelial osteoprotegerin secretion: role of protein kinase A and C Am J Physiol Renal Physiol, January 1, 2009; 296(1): F60 - F66. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Montecucco and F. Mach Common inflammatory mediators orchestrate pathophysiological processes in rheumatoid arthritis and atherosclerosis Rheumatology, January 1, 2009; 48(1): 11 - 22. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Atkinson Age-related medial elastocalcinosis in arteries: mechanisms, animal models, and physiological consequences J Appl Physiol, November 1, 2008; 105(5): 1643 - 1651. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Shroff, V. Shah, M. P. Hiorns, M. Schoppet, L. C. Hofbauer, G. Hawa, L. J. Schurgers, A. Singhal, I. Merryweather, P. Brogan, et al. The circulating calcification inhibitors, fetuin-A and osteoprotegerin, but not Matrix Gla protein, are associated with vascular stiffness and calcification in children on dialysis Nephrol. Dial. Transplant., October 1, 2008; 23(10): 3263 - 3271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. F Escobar-Morreale, J. I Botella-Carretero, M. A. Martinez-Garcia, M. Luque-Ramirez, F. Alvarez-Blasco, and J. L S. Millan Serum osteoprotegerin concentrations are decreased in women with the polycystic ovary syndrome Eur. J. Endocrinol., September 1, 2008; 159(3): 225 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Mandelbrot, P. W. Santos, R. K. Burt, Y. Oyama, G. A. Block, S. N. Ahya, R. M. Rosa, and A. E. Traynor Resolution of SLE-related soft-tissue calcification following haematopoietic stem cell transplantation Nephrol. Dial. Transplant., August 1, 2008; 23(8): 2679 - 2684. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. L. Demer and Y. Tintut Vascular Calcification: Pathobiology of a Multifaceted Disease Circulation, June 3, 2008; 117(22): 2938 - 2948. [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. Kearns, S. Khosla, and P. J. Kostenuik Receptor Activator of Nuclear Factor {kappa}B Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease Endocr. Rev., April 1, 2008; 29(2): 155 - 192. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Arterial calcifications and increased expression of vitamin D receptor targets in mice lacking TIF1{alpha} PNAS, February 19, 2008; 105(7): 2598 - 2603.
|
|
|
|
|
|
S. Morony, Y. Tintut, Z. Zhang, R. C. Cattley, G. Van, D. Dwyer, M. Stolina, P. J. Kostenuik, and L. L. Demer Osteoprotegerin Inhibits Vascular Calcification Without Affecting Atherosclerosis in ldlr( / ) Mice Circulation, January 22, 2008; 117(3): 411 - 420. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Al-Aly, J.-S. Shao, C.-F. Lai, E. Huang, J. Cai, A. Behrmann, S.-L. Cheng, and D. A. Towler Aortic Msx2-Wnt Calcification Cascade Is Regulated by TNF-{alpha} Dependent Signals in Diabetic Ldlr / Mice Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2589 - 2596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Stompor AN OVERVIEW OF THE PATHOPHYSIOLOGY OF VASCULAR CALCIFICATION IN CHRONIC KIDNEY DISEASE Perit. Dial. Int., June 1, 2007; 27(Supplement_2): S215 - S222. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R Shetty, A Pepin, A Charest, J Perron, D Doyle, P Voisine, F Dagenais, P Pibarot, and P Mathieu Expression of bone-regulatory proteins in human valve allografts Heart, September 1, 2006; 92(9): 1303 - 1308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Westenfeld, M. Ketteler, and V. M. Brandenburg Anti-RANKL therapy--implications for the bone-vascular-axis in CKD? Denosumab in post-menopausal women with low bone mineral density Nephrol. Dial. Transplant., August 1, 2006; 21(8): 2075 - 2077. [Full Text] [PDF]
|
|
|
|
 |
|
 G.-d. Xiang, L. Xu, L.-s. Zhao, L. Yue, and J. Hou The relationship between plasma osteoprotegerin and endothelium-dependent arterial dilation in type 2 diabetes. Diabetes, July 1, 2006; 55(7): 2126 - 2131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Qin, M. A. Corriere, L. M. Matrisian, and R. J. Guzman Matrix Metalloproteinase Inhibition Attenuates Aortic Calcification Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1510 - 1516. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. V. Anand, A. Lahiri, E. Lim, D. Hopkins, and R. Corder The Relationship Between Plasma Osteoprotegerin Levels and Coronary Artery Calcification in Uncomplicated Type 2 Diabetic Subjects J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1850 - 1857. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Price, W. Si Chan, D. M. Jolson, and M. K. Williamson The Elastic Lamellae of Devitalized Arteries Calcify When Incubated in Serum: Evidence for a Serum Calcification Factor Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 1079 - 1085. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. L. Demer and Y. Tintut Pitting Phosphate Transport Inhibitors Against Vascular Calcification Circ. Res., April 14, 2006; 98(7): 857 - 859. [Full Text] [PDF]
|
|
|
|
 |
|
 I. Lopez, E. Aguilera-Tejero, F. J. Mendoza, Y. Almaden, J. Perez, D. Martin, and M. Rodriguez Calcimimetic R-568 Decreases Extraosseous Calcifications in Uremic Rats Treated with Calcitriol J. Am. Soc. Nephrol., March 1, 2006; 17(3): 795 - 804. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Rogers and R. Eastell Circulating Osteoprotegerin and Receptor Activator for Nuclear Factor {kappa}B Ligand: Clinical Utility in Metabolic Bone Disease Assessment J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6323 - 6331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Y. Qunibi Reducing the Burden of Cardiovascular Calcification in Patients with Chronic Kidney Disease J. Am. Soc. Nephrol., November 1, 2005; 16(11_suppl_2): S95 - S102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. H. Dao, R. Essalihi, C. Bouvet, and P. Moreau Evolution and modulation of age-related medial elastocalcinosis: Impact on large artery stiffness and isolated systolic hypertension Cardiovasc Res, May 1, 2005; 66(2): 307 - 317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.E. Norman and J.T. Powell Vitamin D, Shedding Light on the Development of Disease in Peripheral Arteries Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 39 - 46. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Giachelli Vascular Calcification Mechanisms J. Am. Soc. Nephrol., December 1, 2004; 15(12): 2959 - 2964. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Collin-Osdoby Regulation of Vascular Calcification by Osteoclast Regulatory Factors RANKL and Osteoprotegerin Circ. Res., November 26, 2004; 95(11): 1046 - 1057. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bern Observations on Possible Effects of Daily Vitamin K Replacement, Especially Upon Warfarin Therapy JPEN J Parenter Enteral Nutr, November 1, 2004; 28(6): 388 - 398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Doherty, L. A. Fitzpatrick, D. Inoue, J.-H. Qiao, M. C. Fishbein, R. C. Detrano, P. K. Shah, and T. B. Rajavashisth Molecular, Endocrine, and Genetic Mechanisms of Arterial Calcification Endocr. Rev., August 1, 2004; 25(4): 629 - 672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Soufi, M. Schoppet, A. M. Sattler, M. Herzum, B. Maisch, L. C. Hofbauer, and J. R. Schaefer Osteoprotegerin Gene Polymorphisms in Men with Coronary Artery Disease J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3764 - 3768. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Schoppet, N. Al-Fakhri, F. E. Franke, N. Katz, P. J. Barth, B. Maisch, K. T. Preissner, and L. C. Hofbauer Localization of Osteoprotegerin, Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand, and Receptor Activator of Nuclear Factor-{kappa}B Ligand in Monckeberg's Sclerosis and Atherosclerosis J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 4104 - 4112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. C. Hofbauer and M. Schoppet Clinical Implications of the Osteoprotegerin/RANKL/RANK System for Bone and Vascular Diseases JAMA, July 28, 2004; 292(4): 490 - 495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Abedin, Y. Tintut, and L. L. Demer Vascular Calcification: Mechanisms and Clinical Ramifications Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1161 - 1170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kiechl, G. Schett, G. Wenning, K. Redlich, M. Oberhollenzer, A. Mayr, P. Santer, J. Smolen, W. Poewe, and J. Willeit Osteoprotegerin Is a Risk Factor for Progressive Atherosclerosis and Cardiovascular Disease Circulation, May 11, 2004; 109(18): 2175 - 2180. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Price, H. H. June, N. J. Hamlin, and M. K. Williamson Evidence for a Serum Factor That Initiates the Re-calcification of Demineralized Bone J. Biol. Chem., April 30, 2004; 279(18): 19169 - 19180. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Samelson, D. P. Kiel, K. E. Broe, Y. Zhang, L. A. Cupples, M. T. Hannan, P. W. F. Wilson, D. Levy, S. A. Williams, and V. Vaccarino Metacarpal Cortical Area and Risk of Coronary Heart Disease: The Framingham Study Am. J. Epidemiol., March 15, 2004; 159(6): 589 - 595. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Doherty, L. A. Fitzpatrick, A. Shaheen, T. B. Rajavashisth, and R. C. Detrano Genetic Determinants of Arterial Calcification Associated With Atherosclerosis Mayo Clin. Proc., February 1, 2004; 79(2): 197 - 210. [Abstract] [PDF]
|
|
|
|
|
|
P. A. Price, M. K. Williamson, T. M. T. Nguyen, and T. N. Than Serum Levels of the Fetuin-Mineral Complex Correlate with Artery Calcification in the Rat J. Biol. Chem., January 16, 2004; 279(3): 1594 - 1600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-S. Shao, S.-L. Cheng, N. Charlton-Kachigian, A. P. Loewy, and D. A. Towler Teriparatide (Human Parathyroid Hormone (1-34)) Inhibits Osteogenic Vascular Calcification in Diabetic Low Density Lipoprotein Receptor-deficient Mice J. Biol. Chem., December 12, 2003; 278(50): 50195 - 50202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Schoppet, A. M. Sattler, J. R. Schaefer, M. Herzum, B. Maisch, and L. C. Hofbauer Increased Osteoprotegerin Serum Levels in Men with Coronary Artery Disease J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1024 - 1028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Price, H. H. June, J. R. Buckley, and M. K. Williamson SB 242784, a Selective Inhibitor of the Osteoclastic V-H+-ATPase, Inhibits Arterial Calcification in the Rat Circ. Res., September 20, 2002; 91(6): 547 - 552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. DOHERTY, H. UZUI, L. A. FITZPATRICK, P. V. TRIPATHI, C. R. DUNSTAN, K. ASOTRA, and T. B. RAJAVASHISTH Rationale for the role of osteoclast-like cells in arterial calcification FASEB J, April 1, 2002; 16(6): 577 - 582. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Schoppet, K. T. Preissner, and L. C. Hofbauer RANK Ligand and Osteoprotegerin: Paracrine Regulators of Bone Metabolism and Vascular Function Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 549 - 553. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Schoppet, K. T. Preissner, and L. C. Hofbauer RANK Ligand and Osteoprotegerin: Paracrine Regulators of Bone Metabolism and Vascular Function Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 549 - 553. [Abstract] [Full Text] [PDF]
|
|