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Vascular calcification and its relation to bone calcification: Possible underlying mechanisms

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Journal of Nuclear Cardiology Aims and scope

Summary

Significant scientific and clinical advances have been achieved in the study of vascular calcification during the last 10 years. Vascular calcification occurs frequently in atheromas and carries significant risk for future cardiac events due to stenotic and hemodynamic effects. The constituents of bone matrix and mineralization are present in atherosclerotic lesions, and a population of cells that secrete these products in vitro has been identified. The phenotype of these cells and their capacity to secrete osteoid are under the control of numerous inflammatory mediators and are thought to be regulated by similar molecular mechanisms as osteogenesis. Clinically, further studies are required to precisely define the prevalence of vascular calcification and its correlation with atherosclerotic disease, including risk factors for atherothrombotic disease such as smoking, diabetes, dyslipidemia, and sedentary lifestyle. Many other issues remain to be addressed including the following: the origin of subpopulations of progenitor cells within the arterial tree, other differentiation capacity of these progenitor cells, factors that control their migration, and the presence of a common molecular regulatory motif of bone development linking atherogenesis and osteoporosis.

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References

  1. Favus MJ, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 1999. p. 3–29.

    Google Scholar 

  2. Schinke T, McKee MD, Karsenty G. Extracellular matrix calcifi- cation: where is the action? Nat Genet 1999;21:150–1.

    Article  PubMed  CAS  Google Scholar 

  3. Wayhs R, Zelinger A, Raggi P. High coronary artery calcium scores pose an extremely elevated risk for hard events. J Am Coll Cardiol 2002;39:225–30.

    Article  PubMed  Google Scholar 

  4. Bostrom K. Regulatory mechanisms in vascular calcification. Crit Rev Eukaryot Gene Expr 2000;12:151–8.

    Google Scholar 

  5. Huang H, Virmani R, Younis H, et al. The impact of calcification on the biomechanical stability of atherosclerotic plaques. Circulation 2001;103:1051–6.

    PubMed  CAS  Google Scholar 

  6. Richardson PD, Davies MJ, Born GV. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet 1989;2(8669):941–4.

    Article  PubMed  CAS  Google Scholar 

  7. Beckman JA, Ganz J, Creager MA, Ganz P, Kinlay S. Relationship of clinical presentation and calcification of culprit coronary artery stenoses. Arterioscler Thromb Vasc Biol 2001;21:1618- 22.

    Article  PubMed  CAS  Google Scholar 

  8. Ohtsuka S, Kakihana M, Watanabe H, Sugishita Y. Chronically decreased aortic distensibility causes deterioration of coronary perfusion during increased left ventricular contraction. J Am Coll Cardiol 1994;24:1406–14.

    Article  PubMed  CAS  Google Scholar 

  9. Schmid K, McSharry WO, Pameijer CH, Binette JP. Chemical and physicochemical studies on the mineral deposits of the human atherosclerotic aorta. Atherosclerosis 1980;37:199–210.

    Article  PubMed  CAS  Google Scholar 

  10. Janzen J, Vuong PN. Arterial calcifications: morphological aspects and their pathological implications. Z Kardiol 2001;90(Suppl 3):6–11.

    PubMed  Google Scholar 

  11. Bostrom K, Watson KE, Horn S, et al. Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest 1993; 91:1800–9.

    Article  PubMed  CAS  Google Scholar 

  12. Watson K, Bostrom K, Ravindranath R, et al. TGFβ1 and 25-hydroxycholesterol stimulate osteoblast-like vascular cells to calcify. J Clin Invest 1994;93:2106–13.

    Article  PubMed  CAS  Google Scholar 

  13. Tintut Y, Parhami F, Bostrom K, Jackson SM, Demer LL. cAMP stimulates osteoblast-like differentiation of calcifying vascular cells. J Biol Chem 1998;273:7547–53.

    Article  PubMed  CAS  Google Scholar 

  14. Mori K, Shioi A, Jono S, Nishizawa Y, Morll H. Dexamethasone enhances in vitro vascular calcification by promoting osteoblastic differentiation of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1999;19:2112–8.

    PubMed  CAS  Google Scholar 

  15. Proudfoot D, Skepper JN, Shanahan CM, Weissberg PL. Calcification of human vascular cells in vitro is correlated with high levels of matrix Gla protein and low levels of osteopontin expression. Arterioscler Thromb Vasc Biol 1998;18:379–88.

    PubMed  CAS  Google Scholar 

  16. Jono S, Peinado C, Giachelli CM. Phosphorylation of osteopontin is required for inhibition of vascular smooth muscle cell calcification. J Biol Chem 2000;275:20197–203.

    Article  PubMed  CAS  Google Scholar 

  17. Mohler ER III, Chawla MK, Chang AW, et al. Identification and characterization of calcifying valve cells from human and canine aortic valves. J Heart Valve Dis 1999;8:254–60.

    PubMed  Google Scholar 

  18. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284(5411):143–77.

    Article  PubMed  CAS  Google Scholar 

  19. Tintut Y, Patel J, Parhami F, Demer LL. Tumor necrosis factoralpha promotes in vitro calcification of vascular cells via the cAMP pathway. Circulation 2000;102:2636–42.

    PubMed  CAS  Google Scholar 

  20. Tintut Y, Patel J, Territo M, et al. Monocyte/Macrophage regulation of vascular calcification in vitro. Circulation 2002; 105:650–5.

    Article  PubMed  CAS  Google Scholar 

  21. Mody N, Parhami F, Sarafian T, Demer LL. Oxidative stress modulates osteoblastic differentiation of vascular and bone cells. Free Rad Biol Med 2001;31:509–19.

    Article  PubMed  CAS  Google Scholar 

  22. Schor AM, Allen TD, Canfield AE, Sloan P, Schor SL. Pericytes derived from the retinal microvasculature undergo calcification in vitro. J Cell Sci 1990;97:449–61.

    PubMed  Google Scholar 

  23. Rodan GA, Harada S. The missing bone. Cell 1997;89:677–80.

    Article  PubMed  CAS  Google Scholar 

  24. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G. Osf2/ Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 1997, 89:747–54.

    Article  PubMed  CAS  Google Scholar 

  25. Nakashima K, Zhou X, Kunkel G, et al. The novel zinc fingercontaining transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 2002;108:17–29.

    Article  PubMed  CAS  Google Scholar 

  26. Gerhart TN, Kirker-Head CA, Kriz MJ, et al. Healing of large mid-femoral segmental defects in sheep using recombinant human bone morphogenetic protein (BMP-2) [abstract]. Trans Orthop Res Soc 1991;16:172.

    Google Scholar 

  27. Willette RN, Gu JL, Lysko PG, et al. BMP-2 gene expression and effects on human vascular smooth muscle cells. J Vasc Res 1999;36:120–5.

    Article  PubMed  CAS  Google Scholar 

  28. Luo G, Ducy P, McKee MD, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997;386:78–81.

    Article  PubMed  CAS  Google Scholar 

  29. Zebboudj AF, Imura M, Bostrom K. Matrix GLA protein, a regulatory protein for bone morphogenetic protein-2. J Biol Chem 2002;277:4388–94.

    Article  PubMed  CAS  Google Scholar 

  30. Bostrom K, Tsao D, Shen S, Wang Y, Demer LL. Matrix Gla protein modulates differentiation induced by bone morphogenetic protein-2 in C3H10T1/2 cells. J Biol Chem 2001;276:14044–52.

    PubMed  CAS  Google Scholar 

  31. Watson KE, Parhami F, Shin V, Demer LL. Fibronectin and collagen I matrices promote calcification of vascular cells in vitro, whereas collagen IV is inhibitory. Arterioscler Thromb Vasc Biol 1998;18:1964–71.

    PubMed  CAS  Google Scholar 

  32. Bellows CG, Aubin JE, Heersch JNM. Initiation and progression of mineralization of bone nodules formed in vitro: the role of alkaline phosphatase and organic phosphate. Bone Miner 1991;14:27–400.

    Article  PubMed  CAS  Google Scholar 

  33. Klein BY, Gal I, Segal D. Studies of the levamisole inhibitory effect on rat stromal-cell commitment to mineralization. J Cell Biochem 1993;53:114–21.

    Article  PubMed  CAS  Google Scholar 

  34. Hui M, Li SQ, Holmyard D, Cheng P-T. Stable transfection of nonosteogenic cell lines with tissue nonspecific alkaline phosphatase enhances mineral deposition both in the presence and absence of beta-glycerophosphate: possible role for alkaline phosphatase in pathological mineralization. Calcif Tissue Int 1997;60:467–72.

    Article  PubMed  CAS  Google Scholar 

  35. Parhami F, Tintut Y, Ballard A, Fogelman AM, Demer LL. Leptin enhances the calcification of vascular cells: artery wall as a target of leptin. Circ Res 2001;88:954–60.

    Article  PubMed  CAS  Google Scholar 

  36. Shioi A, Nishizawa Y, Jono S, et al. Beta-glycerophosphate accelerates calcification in cultured bovine vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1995;15:2003–9.

    PubMed  CAS  Google Scholar 

  37. Hunter GK, Kyle CL, Goldberg HA. Modulation of crystal formation by bone phosphoproteins: structural specificity of the osteopontin-mediated inhibition of hydroxyapatite formation. Biochem J 1994;300:723–8.

    PubMed  CAS  Google Scholar 

  38. Ross FP, Chappel J, Alvarez JI, et al. Interaction between the bone matrix proteins osteopontin and bone sialoprotein and the osteoclast integrin alpha v beta 3 potentiate bone resorption. J Biol Chem 1993;268:9901–7.

    PubMed  CAS  Google Scholar 

  39. Aubin JE, Turksin K, Heersche JNM. Osteoblastic cell lineage. In: Noda M, editor. Cellular and molecular biology of bone. San Diego: Academic Press; 1993. p. 2–45.

    Google Scholar 

  40. O’Brien ER, Garvin MR, Stewart DK, et al. Osteopontin is synthesized by macrophage, smooth muscle, and endothelial cells in primary and restenotic human coronary atherosclerotic plaques. Arterioscler Thromb 1994;14:1648–56.

    PubMed  CAS  Google Scholar 

  41. Rittling SR, Matsumoto HN, McKee MD, et al. Mice lacking osteopontin show normal development and bone structure but display altered osteoclast formation in vitro. J Bone Miner Res 1998;13:1101–11.

    Article  PubMed  CAS  Google Scholar 

  42. Thiede MA, Smock SL, Petersen DN, et al. Presence of messenger ribonucleic acid encoding osteocalcin, a marker of bone turnover, in bone marrow megakaryocytes and peripheral blood platelets. Endocrinology 1994;135:929–37.

    Article  PubMed  CAS  Google Scholar 

  43. Ducy P, Desbois C, Boyce B, et al. Increased bone formation in osteocalcin-deficient mice. Nature 1996;382:448–52.

    Article  PubMed  CAS  Google Scholar 

  44. Shanahan CM, Cary NR, Metcalfe JC, Weissberg PL. High expression of genes for calcification-regulating proteins in human atherosclerotic plaques. J Clin Invest 1994;93:2393–402.

    Article  PubMed  CAS  Google Scholar 

  45. Herrmann S-M, Whatling C, Brand E, et al. Polymorphisms of the human matrix Gla protein (MGP) gene, vascular calcification, and myocardial infarction. Arterioscler Thromb Vasc Biol 2000;20:2386–933.

    PubMed  CAS  Google Scholar 

  46. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89:309–19.

    Article  PubMed  CAS  Google Scholar 

  47. Bucay N, Sarosi I, Dunstan CR, et al. Osteoprotegerin deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998;12:1260–8.

    Article  PubMed  CAS  Google Scholar 

  48. Parhami F, Garfinkel A, Demer LL. Role of Lipids in Osteoporosis. Arterioscler Thromb Vasc Biol 2000;20:2346–8.

    PubMed  CAS  Google Scholar 

  49. The blood supply of bone. An approach to bone biology. London: Murray Brookes, Butterworth & Co Ltd; 1971.

  50. Parhami F, Morrow AD, Balucan J, et al. Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. Arterioscler Thromb Vasc Biol 1997;17:680–7.

    PubMed  CAS  Google Scholar 

  51. Parhami F, Tintut Y, Beamer WG, et al. Atherogenic high-fat diet reduces bone mineralization in mice. J Bone Miner Res 2001;16:182–88.

    Article  PubMed  CAS  Google Scholar 

  52. van’t Hof RJ, Ralston SH. Nitric oxide and bone. Immunology 2001;103:255–61.

    Article  Google Scholar 

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Authors and Affiliations

  1. Departments of Medicine and Physiology, David Geffen School of Medicine at University of California Los Angeles, 47-123 CHS, Box 951679, 90095-1679, Los Angeles, Calif

    Nilam Mody, Yin Tintut, Kristen Radcliff & Linda L. Demer

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  1. Nilam Mody
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  2. Yin Tintut
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  3. Kristen Radcliff
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  4. Linda L. Demer
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Correspondence to Linda L. Demer.

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Mody, N., Tintut, Y., Radcliff, K. et al. Vascular calcification and its relation to bone calcification: Possible underlying mechanisms. J Nucl Cardiol 10, 177–183 (2003). https://doi.org/10.1067/mnc.2003.0012

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