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
L. M. Rasmussen, M. D.
Department of Clinical Biochemistry
Norrebrogade 44 · Åarhus Sygehus · 8000 Åarhus · Denmark
eMail: lmr@dadlnet.dk
