Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species

 

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Summary

Matrix γ-carboxyglutamate (Gla) protein (MGP) is an important local inhibitor of vascular calcification, which can undergo two post-translational modifications: vitamin K-dependent γ-glutamate carboxylation and serine phosphorylation. While carboxylation is thought to have effects upon binding of calcium-ions, phosphorylation is supposed to affect the cellular release of MGP. Since both modifications can be exerted incompletely, various MGP species can be detected in the circulation. MGP levels were measured with two commercially available competitive and two novel sandwich assays in healthy controls, in patients with rheumatic disease, aortic valve disease, and end-stage renal disease, as well as in volunteers after vitamin K supplementation (VKS) and treatment with vitamin K antagonists (VKA). Major differences were found between the MGP assays, including significantly different behaviour with regard to vascular disease and the response to VKA and VKS. The dual-antibody assay measuring non-phosphorylated, non-carboxylated MGP (dp-ucMGP) was particularly sensitive for these changes and would be suited to assess the vascular vitamin K status. We conclude that the different assays for particular circulating MGP species allows the assessment of various aspects of the MGP system.

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• 1 Schurgers LJ, Cranenburg ECM, Vermeer C. Matrix Gla-protein: The calcification inhibitor in need of vitamin K.. Thromb Haemost 2008; 100: 593-603.
  Article in Thieme ConnectPubMedGoogle Scholar
• 2 El-Maadawy S, Kaartinen MT, Schinke T. et al. Cartilage formation and calcification in arteries of mice lacking matrix Gla protein.. Connect Tissue Res 2003; 44: 272-278.
  CrossrefPubMedGoogle Scholar
• 3 Luo G, D’Souza R, Hogue D. et al. The matrix Gla protein gene is a marker of the chondrogenesis cell lineage during mouse development.. J Bone Miner Res 1995; 10: 325-334.
  PubMedGoogle Scholar
• 4 Wallin R, Cain D, Sane DC. Matrix Gla protein synthesis and gamma-carboxylation in the aortic vessel wall and proliferating vascular smooth muscle cells--a cell system which resembles the system in bone cells.. Thromb Haemost 1999; 82: 1764-1767.
  Article in Thieme ConnectPubMedGoogle Scholar
• 5 Price PA, Rice JS, Williamson MK. Conserved phosphorylation of serines in the Ser-X-Glu/Ser(P) sequences of the vitamin K-dependent matrix Gla protein from shark, lamb, rat, cow, and human.. Protein Sci 1994; 3: 822-830.
  PubMedGoogle Scholar
• 6 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.
  CrossrefPubMedGoogle Scholar
• 7 Price PA, Williamson MK. Primary structure of bovine matrix Gla protein, a new vitamin K-dependent bone protein.. J Biol Chem 1985; 260: 14971-14975.
  PubMedGoogle Scholar
• 8 Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves.. Arterioscler Thromb Vasc Biol 1998; 18: 1400-1407.
  CrossrefPubMedGoogle Scholar
• 9 Price PA, Chan WS, Jolson DM. et al. The elastic lamellae of devitalized arteries calcify when incubated in serum: evidence for a serum calcification factor.. Arterioscler Thromb Vasc Biol 2006; 26: 1079-1085.
  CrossrefPubMedGoogle Scholar
• 10 Wallin R, Cain D, Hutson SM. et al. Modulation of the binding of matrix Gla protein (MGP) to bone morphogenetic protein-2 (BMP-2).. Thromb Haemost 2000; 84: 1039-1044.
  Article in Thieme ConnectPubMedGoogle Scholar
• 11 Bostrom K, Tsao D, Shen S. et al. Matrix GLA protein modulates differentiation induced by bone morphogenetic protein-2 in C3H10T1/2 cells.. J Biol Chem 2001; 276: 14044-14052.
  CrossrefPubMedGoogle Scholar
• 12 Zebboudj AF, Imura M, Bostrom K. Matrix GLA protein, a regulatory protein for bone morphogenetic protein-2.. J Biol Chem 2002; 277: 4388-4394.
  CrossrefPubMedGoogle Scholar
• 13 Wallin R, Schurgers LJ, Wajih N. Effects of the blood coagulation vitamin K as an inhibitor of arterial calcification.. Thromb Res 2008; 122: 411-417.
  CrossrefPubMedGoogle Scholar
• 14 Wajih N, Borras T, Xue W. et al. Processing and transport of matrix gamma-carboxyglutamic acid protein and bone morphogenetic protein-2 in cultured human vascular smooth muscle cells: evidence for an uptake mechanism for serum fetuin.. J Biol Chem 2004; 279: 43052-43060.
  CrossrefPubMedGoogle Scholar
• 15 Price PA, Faus SA, Williamson MK. Warfarin-induced artery calcification is accelerated by growth and vitamin D.. Arterioscler Thromb Vasc Biol 2000; 20: 317-327.
  CrossrefPubMedGoogle Scholar
• 16 Sweatt A, Sane DC, Hutson SM. et al. Matrix Gla protein (MGP) and bone morphogenetic protein-2 in aortic calcified lesions of aging rats.. J Thromb Haemost 2003; 1: 178-185.
  CrossrefPubMedGoogle Scholar
• 17 Schurgers LJ, Teunissen KJ, Knapen MH. et al. Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification.. Arterioscler Thromb Vasc Biol 2005; 25: 1629-1633.
  CrossrefPubMedGoogle Scholar
• 18 Murshed M, Schinke T, McKee MD. et al. Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins.. J Cell Biol 2004; 165: 625-630.
  CrossrefPubMedGoogle Scholar
• 19 Holden RM, Booth SL. Vascular calcification and chronic kidney diseases; the role of vitamin K.. Nat Clin Pract Nephrol 2007; 3: 522-523.
  CrossrefPubMedGoogle Scholar
• 20 Beulens JW, Bots ML, Atsma F. et al. High dietary menaquinone intake is associated with reduced coronary calcification.. Atherosclerosis 2009; 203: 489-493.
  CrossrefPubMedGoogle Scholar
• 21 Gast GC, de Roos NM, Sluijs I. et al. A high menaquinone intake reduces the incidence of coronary heart disease.. Nutr Metab Cardiovasc Dis 2009; 19: 504-510.
  CrossrefPubMedGoogle Scholar
• 22 Shearer MJ, Newman P. Metabolism and cell biology of vitamin K.. Thromb Haemost 2008; 100: 530-547.
  Article in Thieme ConnectPubMedGoogle Scholar
• 23 Schurgers LJ, Teunissen KJ, Hamulyak K. et al. Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaqui-none-7.. Blood 2007; 109: 3279-3283.
  CrossrefPubMedGoogle Scholar
• 24 Otawara YY, Price PPA. Developmental appearance of matrix GLA protein during calcification in the rat.. J Biol Chem 1986; 261: 10828-10832.
  PubMedGoogle Scholar
• 25 Schurgers LJ, Teunissen KJ, Knapen MH. et al. Characteristics and performance of an immunosorbent assay for human matrix Gla-protein.. Clin Chim Acta 2005; 351: 131-138.
  CrossrefPubMedGoogle Scholar
• 26 Cranenburg EC, Vermeer C, Koos R. et al. The circulating inactive form of Matrix Gla Protein (ucMGP) as a biomarker for cardiovascular calcification.. J Vasc Res 2008; 45: 427-436.
  CrossrefPubMedGoogle Scholar
• 27 Cranenburg ECM, Brandenburg VM, Vermeer C. et al. Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemo-dialysis patients.. Thromb Haemost 2009; 101: 359-366.
  Article in Thieme ConnectPubMedGoogle Scholar
• 28 Koos R, Krueger T, Westenfeld R. et al. Relation of circulating Matrix Gla-Protein and anticoagulation status in patients with aortic valve calcification.. Thromb Haemost 2009; 101: 706-713.
  Article in Thieme ConnectPubMedGoogle Scholar
• 29 Parker BD, Ix JH, Cranenburg EC. et al. Association of kidney function and uncarboxylated matrix Gla protein: Data from the Heart and Soul Study.. Nephrol Dial Transplant 2009; 24: 2095-2101.
  CrossrefPubMedGoogle Scholar
• 30 Braam LA, Dissel P, Gijsbers BL. et al. Assay for human matrix gla protein in serum: potential applications in the cardiovascular field.. Arterioscler Thromb Vasc Biol 2000; 20: 1257-1261.
  CrossrefPubMedGoogle Scholar
• 31 Rosenhek R, Binder T, Porenta G. et al. Predictors of outcome in severe, asymptomatic aortic stenosis.. N Engl J Med 2000; 343: 611-617.
  CrossrefPubMedGoogle Scholar
• 32 Blacher J, Guerin AP, Pannier B. et al. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease.. Hypertension 2001; 38: 938-942.
  CrossrefPubMedGoogle Scholar
• 33 London GM, Guerin AP, Marchais SJ. et al. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.. Nephrol Dial Transplant 2003; 18: 1731-1740.
  CrossrefPubMedGoogle Scholar
• 34 Asanuma Y, Oeser A, Shintani AK. et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus.. N Engl J Med 2003; 349: 2407-2415.
  CrossrefPubMedGoogle Scholar
• 35 Wang S, Yiu KH, Mok MY. et al. Prevalence and extent of calcification over aorta, coronary and carotid arteries in patients with rheumatoid arthritis.. J Intern Med 2009; 266: 445-452.
  CrossrefPubMedGoogle Scholar
• 36 Chung CP, Oeser A, Raggi P. et al. Increased coronary-artery atherosclerosis in rheumatoid arthritis: relationship to disease duration and cardiovascular risk factors.. Arthritis Rheum 2005; 52: 3045-3053.
  CrossrefPubMedGoogle Scholar
• 37 Knapen MH, Schurgers LJ, Vermeer C. Vitamin K(2) supplementation improves hip bone geometry and bone strength indices in postmenopausal women.. Osteoporos Int 2007; 18: 963-972.
  CrossrefPubMedGoogle Scholar
• 38 Bonow RO, Carabello BA, Chatterjee K. et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons.. J Am Coll Cardiol 2006; 48: e1-148.
  CrossrefPubMedGoogle Scholar
• 39 Schurgers LJ, Spronk HM, Soute BA. et al. Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats.. Blood 2007; 109: 2823-2831.
  PubMedGoogle Scholar
• 40 Shroff RC, McNair R, Figg N. et al. Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis.. Circulation 2008; 118: 1748-1757.
  CrossrefPubMedGoogle Scholar
• 41 Sokoll LJ, Booth SL, O’Brien ME. et al. Changes in serum osteocalcin, plasma phylloquinone, and urinary gamma-carboxyglutamic acid in response to altered intakes of dietary phylloquinone in human subjects.. Am J Clin Nutr 1997; 65: 779-784.
  CrossrefPubMedGoogle Scholar
• 42 Sokoll LJ, Sadowski JA. Comparison of biochemical indexes for assessing vitamin K nutritional status in a healthy adult population.. Am J Clin Nutr 1996; 63: 566-573.
  CrossrefPubMedGoogle Scholar
• 43 Geleijnse JM, Vermeer C, Grobbee DE. et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study.. J Nutr 2004; 134: 3100-3105.
  CrossrefPubMedGoogle Scholar
• 44 Schurgers LJ, Aebert H, Vermeer C. et al. Oral anticoagulant treatment: friend or foe in cardiovascular disease?. Blood 2004; 104: 3231-3232.
  CrossrefPubMedGoogle Scholar
• 45 Koos R, Mahnken AH, Muhlenbruch G. et al. Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography.. Am J Cardiol 2005; 96: 747-749.
  CrossrefPubMedGoogle Scholar
• 46 Lerner RG, Aronow WS, Sekhri A. et al. Warfarin use and the risk of valvular calcification.. J Thromb Haemost 2009; 7: 2023-2027.
  CrossrefPubMedGoogle Scholar
• 47 Schurgers LJ, Barreto DV, Barreto FC. et al. The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report.. Clin J Am Soc Nephrol 2010; 5: 568-575.
  CrossrefPubMedGoogle Scholar