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Table of Contents
Vol. 33, No. 1, 2010
Issue release date: March 2010
Section title: Original Paper
Kidney Blood Press Res 2010;33:66–71
(DOI:10.1159/000289575)

Undercarboxylated Osteocalcin Is a Biomarker of Carotid Calcification in Patients with Essential Hypertension

Okura T. · Kurata M. · Enomoto D. · Jotoku M. · Nagao T. · Desilva V.R. · Irita J. · Miyoshi K.-I. · Higaki J.
Department of Integrated Medicine and Informatics, Ehime University Graduate School of Medicine, Toon City, Japan
email Corresponding Author

Abstract

The development of vascular calcification is an active, highly regulated process with similarities to bone formation. Osteocalcin (OC), a vitamin K-dependent protein expressed by osteoblasts, contains 3 γ-carboxyglutamic acid residues derived from the vitamin K-dependent posttranslational modification of glutamic acid residues. Circulating undercarboxylated OC (ucOC) is increased in vitamin K deficiency and serum ucOC is reported to be a clinical marker of vitamin K status. Vitamin K deficiency is associated with vascular calcification as well as osteoporosis. We evaluated the relationship between ucOC and carotid artery calcification in 92 patients with essential hypertension. Ultrasound of the common carotid artery was performed to identify vascular calcification and subjects were divided into 2 groups: a calcification (+) group and a calcification (–) group. Serum creatinine and ucOC levels were higher in the calcification (+) group than in the calcification (–) group and serum ucOC correlated with serum creatinine. To identify the independent determinant factor for carotid artery calcification, we applied both ucOC and estimated glomerular filtration rate as independent factors in logistic regression analysis. Serum ucOC was an independent determinant of carotid calcification, suggesting that circulating ucOC may be an important biomarker of carotid artery calcification.

© 2010 S. Karger AG, Basel


  

Key Words

  • Carotid artery
  • Vascular calcification
  • Undercarboxylated osteocalcin
  • Essential hypertension

References

  1. Farzaneh-Far A, Proudfoot D, Shanahan C, Weissberg PL: Vascular and valvar calcification: recent advances. Heart 2001;85:13–17.
  2. Shanahan CM, Cary NR, Metcalfe JC, Weissberg PL: High expression of genes for calcification-regulating proteins in human atherosclerotic plaques. J Clin Invest 1994;93:2393–2402.
  3. Chenu C, Colucci S, Grano M, Zigrino P, Barattolo R, Zambonin G, Baldini N, Vergnaud P, Delmas PD, Zallone AZ: Osteocalcin induces chemotaxis, secretion of matrix proteins, and calcium-mediated intracellular signaling in human osteoclast-like cells. J Cell Biol 1994;127:1149–1158.
  4. Roy ME, Nishimoto SK, Rho JY, Bhattacharya SK, Lin JS, Pharr GM: Correlations between osteocalcin content, degree of mineralization, and mechanical properties of C. carpio rib bone. J Biomed Mater Res 2001;54:547–553.
  5. Roy ME, Nishimoto SK, Rho JY, Bhattacharya SK, Pharr GM: The distribution of osteocalcin, degree of mineralization, and mechanical properties along the length of Cyprinus carpio rib bone. J Mater Sci Mater Med 2001;12:699–702.
  6. Furie B, Furie BC: Molecular basis of vitamin K-dependent gamma-carboxylation. Blood 1990;75:1753–1762.
  7. Shearer MJ: Vitamin K. Lancet 1995;345:229–234.
  8. Plantalech L, Guillaumont M, Vergnaud P, Leclercq M, Delmas PD: Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women. J Bone Miner Res 1991;6:1211–1216.
  9. Szulc P, Chapuy MC, Meunier PJ, Delmas PD: Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. J Clin Invest 1993;91:1769–1774.
  10. Szulc P, Arlot M, Chapuy MC, Duboeuf F, Meunier PJ, Delmas PD: Serum undercarboxylated osteocalcin correlates with hip bone mineral density in elderly women. J Bone Miner Res 1994;9:1591–1595.
  11. Shea MK, Dallal GE, Dawson-Hughes B, Ordovas JM, O’Donnell CJ, Gundberg CM, Peterson JW, Booth SL: Vitamin K, circulating cytokines, and bone mineral density in older men and women. Am J Clin Nutr 2008;88:356–363.
  12. Bügel S: Vitamin K and bone health in adult humans. Vitam Horm 2008;78:393–416.
  13. Erkkilä AT, Booth SL: Vitamin K intake and atherosclerosis. Curr Opin Lipidol 2008;19:39–42.
  14. Gössl M, Mödder UI, Atkinson EJ, Lerman A, Khosla S: Osteocalcin expression by circulating endothelial progenitor cells in patients with coronary atherosclerosis. J Am Coll Cardiol 2008;52:1314–1325.
  15. Stevens LA, Coresh J, Greene T, Levey AS: Assessing kidney function – measured and estimated glomerular filtration rate. N Engl J Med 2006;354:2473–2483.
  16. Okura T, Watanabe S, Kurata M, Koresawa M, Irita J, Enomoto D, Jotoku M, Miyoshi K, Fukuoka T, Higaki J: Long-term effects of angiotensin II receptor blockade with valsartan on carotid arterial stiffness and hemodynamic alterations in patients with essential hypertension. Clin Exp Hypertens 2008;30:415–422.
  17. Kurata M, Okura T, Watanabe S, Fukuoka T, Higaki J: Osteopontin and carotid atherosclerosis in patients with essential hypertension. Clin Sci (Lond) 2006;111:319–324.
  18. Odink AE, van der Lugt A, Hofman A, Hunink MG, Breteler MM, Krestin GP, Witteman JC: Association between calcification in the coronary arteries, aortic arch and carotid arteries: the Rotterdam study. Atherosclerosis 2007;193:408–413.
  19. Prabhakaran S, Singh R, Zhou X, Ramas R, Sacco RL, Rundek T: Presence of calcified carotid plaque predicts vascular events: the Northern Manhattan Study. Atherosclerosis 2007;195:e197–e201.
  20. Kanazawa I, Yamaguchi T, Yamauchi M, Yamamoto M, Kurioka S, Yano S, Sugimoto T: Adiponectin is associated with changes in bone markers during glycemic control in type 2 diabetes mellitus. J Clin Endocrinol Metab 2009;94:3031–3038.
  21. Wahlgren CM, Zheng W, Shaalan W, Tang J, Bassiouny HS: Human carotid plaque calcification and vulnerability. Relationship between degree of plaque calcification, fibrous cap inflammatory gene expression and symptomatology. Cerebrovasc Dis 2009;27:193–200.
  22. Adijiang A, Goto S, Uramoto S, Nishijima F, Niwa T: Indoxyl sulphate promotes aortic calcification with expression of osteoblast-specific proteins in hypertensive rats. Nephrol Dial Transplant 2008;23:1892–1901.
  23. Vermeer C: Gamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Biochem J 1990;266:625–636.
  24. Vergnaud P, Garnero P, Meunier PJ, Breart G, Kamihagi K, Delmas PD: Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women: the EPIDOS Study. J Clin Endocrinol Metab 1997;82:719–724.
  25. Price PA, Urist MR, Otawara Y: Matrix gla protein, a new gamma-carboxyglutamic acid-containing protein which is associated with the organic matrix of bone. Biochem Biophys Res Commun 1983;117:765–771.
  26. Fraser JD, Otawara Y, Price PA: 1,25-dihydroxyvitamin D3 stimulates the synthesis of matrix gamma-carboxyglutamic acid protein by osteosarcoma cells. Mutually exclusive expression of vitamin K-dependent bone proteins by clonal osteoblastic cell lines. J Biol Chem 1988;263:911–916.
  27. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G: Spontaneous calcification of arteries and cartilage in mice lacking matrix gla protein. Nature 1997;386:78–81.
  28. Schurgers LJ, Spronk HM, Skepper JN, Hackeng TM, Shanahan CM, Vermeer C, Weissberg PL, Proudfoot D: Post-translational modifications regulate matrix gla protein function: importance for inhibition of vascular smooth muscle cell calcification. J Thromb Haemost 2007;5:2503–2511.
  29. Schurgers LJ, Dissel PE, Spronk HM, Soute BA, Dhore CR, Cleutjens JP, Vermeer C: Role of vitamin K and vitamin K-dependent proteins in vascular calcification. Z Kardiol 2001;90(suppl 3):57–63.

    External Resources

  30. Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van der Meer IM, Hofman A, Witteman JC: Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam study. J Nutr 2004;134:3100–3105.
  31. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296–1305.
  32. Levin A, Djurdjev O, Barrett B, Burgess E, Carlisle E, Ethier J, Jindal K, Mendelssohn D, Tobe S, Singer J, Thompson C: Cardiovascular disease in patients with chronic kidney disease: getting to the heart of the matter. Am J Kidney Dis 2001;38:1398–1407.
  33. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB: Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000;342:1478–1483.
  34. Kramer H, Toto R, Peshock R, Cooper R, Victor R: Association between chronic kidney disease and coronary artery calcification: the Dallas heart study. J Am Soc Nephrol 2005;16:507–513.
  35. Merjanian R, Budoff M, Adler S, Berman N, Mehrotra R: Coronary artery, aortic wall, and valvular calcification in nondialyzed individuals with type 2 diabetes and renal disease. Kidney Int 2003;64:263–271.
  36. Takahashi M, Naitou K, Ohishi T, Kushida K, Miura M: Effect of vitamin K and/or D on undercarboxylated and intact osteocalcin in osteoporotic patients with vertebral or hip fractures. Clin Endocrinol 2001;54:219–224.

  

Author Contacts

Takafumi Okura, MD, PhD
Department of Integrated Medicine and Informatics
Ehime University Graduate School of Medicine
Toon City 791-0295 (Japan)
Tel. +81 89 960 5302, Fax +81 89 960 5306, E-Mail okura@m.ehime-u.ac.jp

  

Article Information

Received: September 23, 2009
Accepted: January 19, 2010
Published online: March 2, 2010
Number of Print Pages : 6
Number of Figures : 1, Number of Tables : 3, Number of References : 36

  

Publication Details

Kidney and Blood Pressure Research

Vol. 33, No. 1, Year 2010 (Cover Date: March 2010)

Journal Editor: Tesar V. (Prague)
ISSN: 1420-4096 (Print), eISSN: 1423-0143 (Online)

For additional information: http://www.karger.com/KBR


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

The development of vascular calcification is an active, highly regulated process with similarities to bone formation. Osteocalcin (OC), a vitamin K-dependent protein expressed by osteoblasts, contains 3 γ-carboxyglutamic acid residues derived from the vitamin K-dependent posttranslational modification of glutamic acid residues. Circulating undercarboxylated OC (ucOC) is increased in vitamin K deficiency and serum ucOC is reported to be a clinical marker of vitamin K status. Vitamin K deficiency is associated with vascular calcification as well as osteoporosis. We evaluated the relationship between ucOC and carotid artery calcification in 92 patients with essential hypertension. Ultrasound of the common carotid artery was performed to identify vascular calcification and subjects were divided into 2 groups: a calcification (+) group and a calcification (–) group. Serum creatinine and ucOC levels were higher in the calcification (+) group than in the calcification (–) group and serum ucOC correlated with serum creatinine. To identify the independent determinant factor for carotid artery calcification, we applied both ucOC and estimated glomerular filtration rate as independent factors in logistic regression analysis. Serum ucOC was an independent determinant of carotid calcification, suggesting that circulating ucOC may be an important biomarker of carotid artery calcification.

© 2010 S. Karger AG, Basel


  

Author Contacts

Takafumi Okura, MD, PhD
Department of Integrated Medicine and Informatics
Ehime University Graduate School of Medicine
Toon City 791-0295 (Japan)
Tel. +81 89 960 5302, Fax +81 89 960 5306, E-Mail okura@m.ehime-u.ac.jp

  

Article Information

Received: September 23, 2009
Accepted: January 19, 2010
Published online: March 2, 2010
Number of Print Pages : 6
Number of Figures : 1, Number of Tables : 3, Number of References : 36

  

Publication Details

Kidney and Blood Pressure Research

Vol. 33, No. 1, Year 2010 (Cover Date: March 2010)

Journal Editor: Tesar V. (Prague)
ISSN: 1420-4096 (Print), eISSN: 1423-0143 (Online)

For additional information: http://www.karger.com/KBR


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 9/23/2009
Accepted: 1/19/2010
Published online: 3/2/2010
Issue release date: March 2010

Number of Print Pages: 6
Number of Figures: 1
Number of Tables: 3

ISSN: 1420-4096 (Print)
eISSN: 1423-0143 (Online)

For additional information: http://www.karger.com/KBR


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Farzaneh-Far A, Proudfoot D, Shanahan C, Weissberg PL: Vascular and valvar calcification: recent advances. Heart 2001;85:13–17.
  2. Shanahan CM, Cary NR, Metcalfe JC, Weissberg PL: High expression of genes for calcification-regulating proteins in human atherosclerotic plaques. J Clin Invest 1994;93:2393–2402.
  3. Chenu C, Colucci S, Grano M, Zigrino P, Barattolo R, Zambonin G, Baldini N, Vergnaud P, Delmas PD, Zallone AZ: Osteocalcin induces chemotaxis, secretion of matrix proteins, and calcium-mediated intracellular signaling in human osteoclast-like cells. J Cell Biol 1994;127:1149–1158.
  4. Roy ME, Nishimoto SK, Rho JY, Bhattacharya SK, Lin JS, Pharr GM: Correlations between osteocalcin content, degree of mineralization, and mechanical properties of C. carpio rib bone. J Biomed Mater Res 2001;54:547–553.
  5. Roy ME, Nishimoto SK, Rho JY, Bhattacharya SK, Pharr GM: The distribution of osteocalcin, degree of mineralization, and mechanical properties along the length of Cyprinus carpio rib bone. J Mater Sci Mater Med 2001;12:699–702.
  6. Furie B, Furie BC: Molecular basis of vitamin K-dependent gamma-carboxylation. Blood 1990;75:1753–1762.
  7. Shearer MJ: Vitamin K. Lancet 1995;345:229–234.
  8. Plantalech L, Guillaumont M, Vergnaud P, Leclercq M, Delmas PD: Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women. J Bone Miner Res 1991;6:1211–1216.
  9. Szulc P, Chapuy MC, Meunier PJ, Delmas PD: Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. J Clin Invest 1993;91:1769–1774.
  10. Szulc P, Arlot M, Chapuy MC, Duboeuf F, Meunier PJ, Delmas PD: Serum undercarboxylated osteocalcin correlates with hip bone mineral density in elderly women. J Bone Miner Res 1994;9:1591–1595.
  11. Shea MK, Dallal GE, Dawson-Hughes B, Ordovas JM, O’Donnell CJ, Gundberg CM, Peterson JW, Booth SL: Vitamin K, circulating cytokines, and bone mineral density in older men and women. Am J Clin Nutr 2008;88:356–363.
  12. Bügel S: Vitamin K and bone health in adult humans. Vitam Horm 2008;78:393–416.
  13. Erkkilä AT, Booth SL: Vitamin K intake and atherosclerosis. Curr Opin Lipidol 2008;19:39–42.
  14. Gössl M, Mödder UI, Atkinson EJ, Lerman A, Khosla S: Osteocalcin expression by circulating endothelial progenitor cells in patients with coronary atherosclerosis. J Am Coll Cardiol 2008;52:1314–1325.
  15. Stevens LA, Coresh J, Greene T, Levey AS: Assessing kidney function – measured and estimated glomerular filtration rate. N Engl J Med 2006;354:2473–2483.
  16. Okura T, Watanabe S, Kurata M, Koresawa M, Irita J, Enomoto D, Jotoku M, Miyoshi K, Fukuoka T, Higaki J: Long-term effects of angiotensin II receptor blockade with valsartan on carotid arterial stiffness and hemodynamic alterations in patients with essential hypertension. Clin Exp Hypertens 2008;30:415–422.
  17. Kurata M, Okura T, Watanabe S, Fukuoka T, Higaki J: Osteopontin and carotid atherosclerosis in patients with essential hypertension. Clin Sci (Lond) 2006;111:319–324.
  18. Odink AE, van der Lugt A, Hofman A, Hunink MG, Breteler MM, Krestin GP, Witteman JC: Association between calcification in the coronary arteries, aortic arch and carotid arteries: the Rotterdam study. Atherosclerosis 2007;193:408–413.
  19. Prabhakaran S, Singh R, Zhou X, Ramas R, Sacco RL, Rundek T: Presence of calcified carotid plaque predicts vascular events: the Northern Manhattan Study. Atherosclerosis 2007;195:e197–e201.
  20. Kanazawa I, Yamaguchi T, Yamauchi M, Yamamoto M, Kurioka S, Yano S, Sugimoto T: Adiponectin is associated with changes in bone markers during glycemic control in type 2 diabetes mellitus. J Clin Endocrinol Metab 2009;94:3031–3038.
  21. Wahlgren CM, Zheng W, Shaalan W, Tang J, Bassiouny HS: Human carotid plaque calcification and vulnerability. Relationship between degree of plaque calcification, fibrous cap inflammatory gene expression and symptomatology. Cerebrovasc Dis 2009;27:193–200.
  22. Adijiang A, Goto S, Uramoto S, Nishijima F, Niwa T: Indoxyl sulphate promotes aortic calcification with expression of osteoblast-specific proteins in hypertensive rats. Nephrol Dial Transplant 2008;23:1892–1901.
  23. Vermeer C: Gamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Biochem J 1990;266:625–636.
  24. Vergnaud P, Garnero P, Meunier PJ, Breart G, Kamihagi K, Delmas PD: Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women: the EPIDOS Study. J Clin Endocrinol Metab 1997;82:719–724.
  25. Price PA, Urist MR, Otawara Y: Matrix gla protein, a new gamma-carboxyglutamic acid-containing protein which is associated with the organic matrix of bone. Biochem Biophys Res Commun 1983;117:765–771.
  26. Fraser JD, Otawara Y, Price PA: 1,25-dihydroxyvitamin D3 stimulates the synthesis of matrix gamma-carboxyglutamic acid protein by osteosarcoma cells. Mutually exclusive expression of vitamin K-dependent bone proteins by clonal osteoblastic cell lines. J Biol Chem 1988;263:911–916.
  27. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G: Spontaneous calcification of arteries and cartilage in mice lacking matrix gla protein. Nature 1997;386:78–81.
  28. Schurgers LJ, Spronk HM, Skepper JN, Hackeng TM, Shanahan CM, Vermeer C, Weissberg PL, Proudfoot D: Post-translational modifications regulate matrix gla protein function: importance for inhibition of vascular smooth muscle cell calcification. J Thromb Haemost 2007;5:2503–2511.
  29. Schurgers LJ, Dissel PE, Spronk HM, Soute BA, Dhore CR, Cleutjens JP, Vermeer C: Role of vitamin K and vitamin K-dependent proteins in vascular calcification. Z Kardiol 2001;90(suppl 3):57–63.

    External Resources

  30. Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van der Meer IM, Hofman A, Witteman JC: Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam study. J Nutr 2004;134:3100–3105.
  31. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296–1305.
  32. Levin A, Djurdjev O, Barrett B, Burgess E, Carlisle E, Ethier J, Jindal K, Mendelssohn D, Tobe S, Singer J, Thompson C: Cardiovascular disease in patients with chronic kidney disease: getting to the heart of the matter. Am J Kidney Dis 2001;38:1398–1407.
  33. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB: Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000;342:1478–1483.
  34. Kramer H, Toto R, Peshock R, Cooper R, Victor R: Association between chronic kidney disease and coronary artery calcification: the Dallas heart study. J Am Soc Nephrol 2005;16:507–513.
  35. Merjanian R, Budoff M, Adler S, Berman N, Mehrotra R: Coronary artery, aortic wall, and valvular calcification in nondialyzed individuals with type 2 diabetes and renal disease. Kidney Int 2003;64:263–271.
  36. Takahashi M, Naitou K, Ohishi T, Kushida K, Miura M: Effect of vitamin K and/or D on undercarboxylated and intact osteocalcin in osteoporotic patients with vertebral or hip fractures. Clin Endocrinol 2001;54:219–224.