Osteoprotegerin and Diabetic Macroangiopathy

Abstract

Osteoprotegerin (OPG) is a bone-related protein that is also present in the vasculature. Recent data suggest that it may play a special role in arterial disease among patients with diabetes. Diabetic macroangiopathy is characterized by a series of diffuse, non-atherosclerotic alterations that hypothetically increase the vulnerability of the vessel wall to atherogenic processes. One prominent feature of the macroangiopathy is linear media calcifications, which have been found to impose a strong risk of future cardiovascular events in epidemiological studies. The mechanisms behind the development of calcifications are unknown, but may be related to the occurrence of diffuse matrix alterations in the arterial wall in diabetes. Interestingly, we have recently observed that the amounts of OPG are increased in the tunica media in arterial tissue from diabetic patients. OPG has been linked to vascular calcifications in immunohistochemical analysis of atherosclerotic tissue and experimental studies on OPG knockout mice. Thus, it is possible that increased arterial OPG concentrations reflect an osteogenic transformation of the vasculature in patients with diabetes as an aspect of diabetic macroangiopathy. This review will evaluate data about OPG in the vasculature and focus on a possible role of OPG in the arterial wall in diabetes.

Key words

Atherosclerosis · Diabetes · Vascular calcification · Trance · Trail

References

• 1 Simonet W S, Lacey D L, Dunstan C R, Kelley M, Chang M S, Luthy R, Nguyen H Q, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan H L, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes T M, Hill D, Pattison W, Campbell P, Boyle W J. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.  Cell. 1997;  89 309-319
• 2 Lacey D L, Timms E, Tan H L, Kelley M J, Dunstan C R, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian Y X, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle W J. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation.  Cell. 1998;  93 165-176
• 3 Shipman C M, Croucher P I. Osteoprotegerin is a soluble decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand and can function as a paracrine survival factor for human myeloma cells.  Cancer Res. 2003;  63 912-916
• 4 Emery J G, McDonnell P, Burke M B, Deen K C, Lyn S, Silverman C, Dul E, Appelbaum E R, Eichman C, DiPrinzio R, Dodds R A, James I E, Rosenberg M, Lee J C, Young P R. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL.  J Biol Chem. 1998;  273 14 363-14 367
• 5 Kwon B, Youn B S, Kwon B S. Functions of newly identified members of the tumor necrosis factor receptor/ligand superfamilies in lymphocytes.  Curr Opin Immunol. 1999;  11 340-345
• 6 Bucay N, Sarosi I, Dunstan C R, Morony S, Tarpley J, Capparelli C, Scully S, Tan H L, Xu W, Lacey D L, Boyle W J, Simonet W S. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification.  Genes Dev. 1998;  12 1260-1268
• 7 Min H, Morony S, Sarosi I, Dunstan C R, Capparelli C, Scully S, Van G, Kaufman S, Kostenuik P J, Lacey D L, Boyle W J, Simonet W S. Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis.  J Exp Med. 2000;  192 463-474
• 8 Price P A, June H H, Buckley J R, Williamson M K. Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D.  Arterioscler Thromb Vasc Biol. 2001;  21 1610-1616
• 9 Dhore C R, Cleutjens J P, Lutgens E, Cleutjens K B, Geusens P P, Kitslaar P J, Tordoir J H, Spronk H M, Vermeer C, Daemen M J. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques.  Arterioscler Thromb Vasc Biol. 2001;  21 1998-2003
• 10 Schoppet M, Al Fakhri N, Franke F E, Katz N, Barth P J, Maisch B, Preissner K T, Hofbauer L C. Localization of osteoprotegerin, tumor necrosis factor-related apoptosis-inducing ligand, and receptor activator of nuclear factor-kappaB ligand in Monckeberg’s sclerosis and atherosclerosis.  J Clin Endocrinol Metab. 2004;  89 4104-4112
• 11 Golledge J, McCann M, Mangan S, Lam A, Karan M. Osteoprotegerin and osteopontin are expressed at high concentrations within symptomatic carotid atherosclerosis.  Stroke. 2004;  35 1636-1641
• 12 Tyson K L, Reynolds J L, McNair R, Zhang Q, Weissberg P L, Shanahan C M. Osteo/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification.  Arterioscler Thromb Vasc Biol. 2003;  23 489-494
• 13 Lehto S, Niskanen L, Suhonen M, Ronnemaa T, Laakso M. Medial artery calcification. A neglected harbinger of cardiovascular complications in non-insulin-dependent diabetes mellitus.  Arterioscler Thromb Vasc Biol. 1996;  16 978-983
• 14 Neubauer B. A quantitative study of peripheral arterial calcification and glucose tolerance in elderly diabetics and non-diabetics.  Diabetologia. 1971;  7 409-413
• 15 Niskanen L, Siitonen O, Suhonen M, Uusitupa M I. Medial artery calcification predicts cardiovascular mortality in patients with NIDDM.  Diabetes Care. 1994;  17 1252-1256
• 16 Olesen P, Ledet T, Rasmussen L M. Arterial osteoprotegerin: Increased amounts in diabetes and modifiable synthesis from vascular smooth muscle cells by insulin and TNF-alpha.  Diabetologia. 2005;  48 561-568
• 17 Dybdahl H, Ledet T. Diabetic macroangiopathy. Quantitative histopathological studies of the extramural coronary arteries from type 2 (non-insulin-dependent) diabetic patients.  Diabetologia. 1987;  30 882-886
• 18 Heickendorff L, Ledet T, Rasmussen L M. Glycosaminoglycans in the human aorta in diabetes mellitus: a study of tunica media from areas with and without atherosclerotic plaque.  Diabetologia. 1994;  37 286-292
• 19 Rasmussen L M, Ledet T. Aortic collagen alterations in human diabetes mellitus. Changes in basement membrane collagen content and in the susceptibility of total collagen to cyanogen bromide solubilisation.  Diabetologia. 1993;  36 445-453
• 20 Rasmussen L M, Heickendorff L. Accumulation of fibronectin in aortas from diabetic patients. A quantitative immunohistochemical and biochemical study.  Lab Invest. 1989;  61 440-446
• 21 Sims T J, Rasmussen L M, Oxlund H, Bailey A J. The role of glycation cross-links in diabetic vascular stiffening.  Diabetologia. 1996;  39 946-951
• 22 Takemoto M, Yokote K, Nishimura M, Shigematsu T, Hasegawa T, Kon S, Uede T, Matsumoto T, Saito Y, Mori S. Enhanced expression of osteopontin in human diabetic artery and analysis of its functional role in accelerated atherogenesis.  Arterioscler Thromb Vasc Biol. 2000;  20 624-628
• 23 Horwood N J, Elliott J, Martin T J, Gillespie M T. Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells.  Endocrinology. 1998;  139 4743-4746
• 24 Zhang J, Fu M, Myles D, Zhu X, Du J, Cao X, Chen Y E. PDGF induces osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways.  FEBS Lett. 2002;  521 180-184
• 25 Fu M, Zhang J, Lin Y Y, Zhu X, Willson T M, Chen Y E. Activation of peroxisome proliferator-activated receptor gamma inhibits osteoprotegerin gene expression in human aortic smooth muscle cells.  Biochem Biophys Res Commun. 2002;  294 597-601
• 26 Gochuico B R, Zhang J, Ma B Y, Marshak-Rothstein A, Fine A. TRAIL expression in vascular smooth muscle.  Am J Physiol Lung Cell Mol Physiol. 2000;  278 L1045-L1050
• 27 Secchiero P, Zerbinati C, Rimondi E, Corallini F, Milani D, Grill V, Forti G, Capitani S, Zauli G. TRAIL promotes the survival, migration and proliferation of vascular smooth muscle cells.  Cell Mol Life Sci. 2004;  61 1965-1974
• 28 Li J H, Kirkiles-Smith N C, McNiff J M, Pober J S. TRAIL induces apoptosis and inflammatory gene expression in human endothelial cells.  J Immunol. 2003;  171 1526-1533
• 29 Secchiero P, Gonelli A, Carnevale E, Milani D, Pandolfi A, Zella D, Zauli G. TRAIL promotes the survival and proliferation of primary human vascular endothelial cells by activating the Akt and ERK pathways.  Circulation. 2003;  107 2250-2256
• 30 Malyankar U M, Scatena M, Suchland K L, Yun T J, Clark E A, Giachelli C M. Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-dependent survival factor for endothelial cells.  J Biol Chem. 2000;  275 20 959-20 962
• 31 Langdahl B L, Carstens M, Stenkjaer L, Eriksen E F. Polymorphisms in the osteoprotegerin gene are associated with osteoporotic fractures.  J Bone Miner Res. 2002;  17 1245-1255
• 32 Arko B, Prezelj J, Komel R, Kocijancic A, Hudler P, Marc J. Sequence variations in the osteoprotegerin gene promoter in patients with postmenopausal osteoporosis.  J Clin Endocrinol Metab. 2002;  87 4080-4084
• 33 Brandstrom H, Stiger F, Lind L, Kahan T, Melhus H, Kindmark A. A single nucleotide polymorphism in the promoter region of the human gene for osteoprotegerin is related to vascular morphology and function.  Biochem Biophys Res Commun. 2002;  293 13-17
• 34 Brandstrom H, Stiger F, Kahan T, Melhus H, Nystrom F, Ohman K P, Malmqvist K, Lind L, Kindmark A. A single nucleotide polymorphism in the promoter region of the osteoprotegerin gene is related to intima-media thickness of the carotid artery in hypertensive patients. The Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA).  Blood Press. 2004;  13 152-157
• 35 Soufi M, Schoppet M, Sattler A M, Herzum M, Maisch B, Hofbauer L C, Schaefer J R. Osteoprotegerin gene polymorphisms in men with coronary artery disease.  J Clin Endocrinol Metab. 2004;  89 3764-3768
• 36 Browner W S, Lui L Y, Cummings S R. Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women.  J Clin Endocrinol Metab. 2001;  86 631-637
• 37 Stilgren L S, Hegedus L M, Beck-Nielsen H, Abrahamsen B. Osteoprotegerin levels in primary hyperparathyroidism: effect of parathyroidectomy and association with bone metabolism.  Calcif Tissue Int. 2003;  73 210-216
• 38 Schoppet M, Sattler A M, Schaefer J R, Herzum M, Maisch B, Hofbauer L C. Increased osteoprotegerin serum levels in men with coronary artery disease.  J Clin Endocrinol Metab. 2003;  88 1024-1028
• 39 Ueland T, Jemtland R, Godang K, Kjekshus J, Hognestad A, Omland T, Squire I B, Gullestad L, Bollerslev J, Dickstein K, Aukrust P. Prognostic value of osteoprotegerin in heart failure after acute myocardial infarction.  J Am Coll Cardiol. 2004;  44 1970-1976
• 40 Kiechl S, Schett G, Wenning G, Redlich K, Oberhollenzer M, Mayr A, Santer P, Smolen J, Poewe W, Willeit J. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease.  Circulation. 2004;  109 2175-2180
• 41 Erdogan B, Aslan E, Bagis T, Gokcel A, Erkanli S, Bavbek M, Altinors N. Intima-media thickness of the carotid arteries is related to serum osteoprotegerin levels in healthy postmenopausal women.  Neurol Res. 2004;  26 658-661
• 42 Knudsen S T, Foss C H, Poulsen P L, Andersen N H, Mogensen C E, Rasmussen L M. Increased plasma concentrations of osteoprotegerin in type 2 diabetic patients with microvascular complications.  Eur J Endocrinol. 2003;  149 39-42
• 43 Andresen J L, Rasmussen L M, Ledet T. Diabetic macroangiopathy and atherosclerosis.  Diabetes. 1996;  45 Suppl 3 S91-S94