Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Osteoporosis International
Published in: Osteoporosis International 4/2014

01-04-2014 | Original Article

Association of matrix Gla protein gene functional polymorphisms with loss of bone mineral density and progression of aortic calcification

Authors: D. Tuñón-Le Poultel, J. B. Cannata-Andía, P. Román-García, J. B. Díaz-López, E. Coto, C. Gómez, M. Naves-Díaz, I. Rodríguez

Published in: Osteoporosis International | Issue 4/2014

Login to get access

Abstract

Summary

Two matrix Gla protein (MGP) polymorphisms were associated with progression of aortic calcification and femoral neck bone loss in men. All these findings were also functionally corroborated in two vascular and bone in vitro systems indicating that MGP genetic variations can be partly responsible of higher risk of bone loss and vascular calcification.

Introduction

MGP plays an important role in bone and vascular mineralization as confirmed by MGP-deficient murine model. We therefore aimed to find a genetic association among -138T>C, -7G>A, and Thr83Ala MGP single-nucleotide polymorphisms (SNPs), bone loss, and progression of aortic calcification in a randomly selected general population of 296 individuals who participated in the European Vertebral Osteoporosis Study.

Methods

To evaluate the rate of change in bone mineral density (BMD) and the progression of aortic calcification, dual X-ray absorptiometry and lateral spine X-rays were performed at baseline and after 4 years of follow-up. Genotyping for the three polymorphisms was carried out using polymerase chain reaction and restriction fragment length analysis. In addition, functional studies of MGP-7G>A and Thr83Ala SNPs were performed on transiently transfected osteoblast-like UMR-106 and vascular smooth muscle A7r5 cells.

Results

The proportion of men who had lost BMD in the femoral neck was higher among homozygous -7AA and 83Ala-Ala (p = 0.039 and p = 0.009, respectively), and also featured a higher risk of progression of aortic calcifications (OR = 5.6, 95 % CI = 1.2–27.8 and OR = 6.8, 95 % CI = 1.4–32.3, respectively). No effect was observed in women. The MGP-7A allele produced a reduction in luciferase activity compared to MGP-7G: 47 % less in vascular cells and 34 % less in bone cells (p = 0.001 and 0.012, respectively). In vascular cells under calcifying conditions, the MGP 83Thr allele showed a slightly higher, although not significant, inhibition than the MGP 83 Ala allele in calcium content suggesting functional differences between both variants.

Conclusion

These results suggest that MGP genetic variations could predict a higher risk of bone loss and progression of vascular calcification in men.
Appendix
Available only for authorised users
Literature
1.
2.
Schinke T, McKee MD, Kiviranta R, Karsenty G (1998) Molecular determinants of arterial calcification. Ann Med 30:538–541PubMedCrossRef
3.
Schulz E, Arfai K, Liu X, Sayre J, Gilsanz V (2004) Aortic calcification and the risk of osteoporosis and fractures. J Clin Endocrinol Metab 89:4246–4253PubMedCrossRef
4.
Naves M, Rodriguez-Garcia M, Diaz-Lopez JB, Gomez-Alonso C, Cannata-Andia JB (2008) Progression of vascular calcifications is associated with greater bone loss and increased bone fractures. Osteoporos Int 19:1161–1166PubMedCrossRef
5.
Neves KR, Graciolli FG, dos Reis LM, Pasqualucci CA, Moyses RM, Jorgetti V (2004) Adverse effects of hyperphosphatemia on myocardial hypertrophy, renal function, and bone in rats with renal failure. Kidney Int 66:2237–2244PubMedCrossRef
6.
Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G (1997) Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 386:78–81PubMedCrossRef
7.
Price PA, Urist MR, Otawara Y (1983) Matrix Gla protein, a new gamma-carboxyglutamic acid-containing protein which is associated with the organic matrix of bone. Biochem Biophys Res Commun 117:765–771PubMedCrossRef
8.
Roy ME, Nishimoto SK (2002) Matrix Gla protein binding to hydroxyapatite is dependent on the ionic environment: calcium enhances binding affinity but phosphate and magnesium decrease affinity. Bone 31:296–302PubMedCrossRef
9.
Zebboudj AF, Shin V, Bostrom K (2003) Matrix GLA protein and BMP-2 regulate osteoinduction in calcifying vascular cells. J Cell Biochem 90:756–765PubMedCrossRef
10.
Munroe PB, Olgunturk RO, Fryns JP, Van Maldergem L, Ziereisen F, Yuksel B, Gardiner RM, Chung E (1999) Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nat Genet 21:142–144PubMedCrossRef
11.
Meier M, Weng LP, Alexandrakis E, Ruschoff J, Goeckenjan G (2001) Tracheobronchial stenosis in Keutel syndrome. Eur Respir J 17:566–569PubMedCrossRef
12.
Herrmann SM, Whatling C, Brand E et al (2000) Polymorphisms of the human matrix gla protein (MGP) gene, vascular calcification, and myocardial infarction. Arterioscler Thromb Vasc Biol 20:2386–2393PubMedCrossRef
13.
Brancaccio D, Biondi ML, Gallieni M, Turri O, Galassi A, Cecchini F, Russo D, Andreucci V, Cozzolino M (2005) Matrix GLA protein gene polymorphisms: clinical correlates and cardiovascular mortality in chronic kidney disease patients. Am J Nephrol 25:548–552PubMedCrossRef
14.
Crosier MD, Booth SL, Peter I, Dawson-Hughes B, Price PA, O’Donnell CJ, Hoffmann U, Williamson MK, Ordovas JM (2009) Matrix Gla protein polymorphisms are associated with coronary artery calcification in men. J Nutr Sci Vitaminol (Tokyo) 55:59–65CrossRef
15.
Cassidy-Bushrow AE, Bielak LF, Levin AM, Sheedy PF 2nd, Turner ST, Boerwinkle E, Lin X, Kardia SL, Peyser PA (2013) Matrix Gla protein gene polymorphism is associated with increased coronary artery calcification progression. Arterioscler Thromb Vasc Biol 33:645–651PubMedCentralPubMedCrossRef
16.
Misra D, Booth SL, Crosier MD, Ordovas JM, Felson DT, Neogi T (2011) Matrix Gla protein polymorphism, but not concentrations, is associated with radiographic hand osteoarthritis. J Rheumatol 38:1960–1965PubMedCentralPubMedCrossRef
17.
Tsukamoto K, Orimo H, Hosoi T, Miyao M, Yoshida H, Watanabe S, Suzuki T, Emi M (2000) Association of bone mineral density with polymorphism of the human matrix Gla protein locus in elderly women. J Bone Miner Metab 18:27–30PubMedCrossRef
18.
O’Neill TW, Felsenberg D, Varlow J, Cooper C, Kanis JA, Silman AJ (1996) The prevalence of vertebral deformity in European men and women: the European Vertebral Osteoporosis Study. J Bone Miner Res 11:1010–1018PubMedCrossRef
19.
Frye MA, Melton LJ 3rd, Bryant SC, Fitzpatrick LA, Wahner HW, Schwartz RS, Riggs BL (1992) Osteoporosis and calcification of the aorta. Bone Miner 19:185–194PubMedCrossRef
20.
21.
Jono S, Nishizawa Y, Shioi A, Morii H (1998) 1,25-Dihydroxyvitamin D3 increases in vitro vascular calcification by modulating secretion of endogenous parathyroid hormone-related peptide. Circulation 98:1302–1306PubMedCrossRef
22.
Maniatis T, Fistch E, Sambrook J (1989) Molecular cloning. Cold Spring Harbor Laboratory Press, New York
23.
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25:402–408PubMedCrossRef
24.
Cartharius K, Frech K, Grote K, Klocke B, Haltmeier M, Klingenhoff A, Frisch M, Bayerlein M, Werner T (2005) MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics 21:2933–2942PubMedCrossRef
25.
26.
McFarlane SI, Muniyappa R, Shin JJ, Bahtiyar G, Sowers JR (2004) Osteoporosis and cardiovascular disease: brittle bones and boned arteries, is there a link? Endocrine 23:1–10PubMedCrossRef
27.
Cannata-Andia JB, Roman-Garcia P, Hruska K (2011) The connections between vascular calcification and bone health. Nephrol Dial Transplant 26:3429–3436PubMedCrossRef
28.
29.
Naves-Diaz M, Cabezas-Rodriguez I, Barrio-Vazquez S, Fernandez E, Diaz-Lopez JB, Cannata-Andia JB (2012) Low calcidiol levels and risk of progression of aortic calcification. Osteoporos Int 23:1177–1182PubMedCrossRef
30.
Estrada K, Styrkarsdottir U, Evangelou E et al (2012) Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 44:491–501PubMedCentralPubMedCrossRef
31.
Raouf A, Seth A (2000) Ets transcription factors and targets in osteogenesis. Oncogene 19:6455–6463PubMedCrossRef
32.
Ceppioglu SK, Yurdun T, Canbakan M (2011) Assessment of matrix Gla protein, Klotho gene polymorphisms, and oxidative stress in chronic kidney disease. Ren Fail 33:866–874
33.
Gao B, Yasui T, Itoh Y, Tozawa K, Hayashi Y, Kohri K (2007) A polymorphism of matrix Gla protein gene is associated with kidney stones. J Urol 177:2361–2365PubMedCrossRef
34.
Hale JE, Williamson MK, Price PA (1991) Carboxyl-terminal proteolytic processing of matrix Gla protein. J Biol Chem 266:21145–21149PubMed
35.
Kaipatur NR, Murshed M, McKee MD (2008) Matrix Gla protein inhibition of tooth mineralization. J Dent Res 87:839–844PubMedCrossRef
36.
Yagami K, Suh JY, Enomoto-Iwamoto M, Koyama E, Abrams WR, Shapiro IM, Pacifici M, Iwamoto M (1999) Matrix GLA protein is a developmental regulator of chondrocyte mineralization and, when constitutively expressed, blocks endochondral and intramembranous ossification in the limb. J Cell Biol 147:1097–1108PubMedCentralPubMedCrossRef
37.
Barone LM, Owen TA, Tassinari MS, Bortell R, Stein GS, Lian JB (1991) Developmental expression and hormonal regulation of the rat matrix Gla protein (MGP) gene in chondrogenesis and osteogenesis. J Cell Biochem 46:351–365PubMedCrossRef
38.
Reid IR, Evans MC, Ames R, Wattie DJ (1991) The influence of osteophytes and aortic calcification on spinal mineral density in postmenopausal women. J Clin Endocrinol Metab 72:1372–1374PubMedCrossRef
Metadata
Title
Association of matrix Gla protein gene functional polymorphisms with loss of bone mineral density and progression of aortic calcification
Authors
D. Tuñón-Le Poultel
J. B. Cannata-Andía
P. Román-García
J. B. Díaz-López
E. Coto
C. Gómez
M. Naves-Díaz
I. Rodríguez
Publication date
01-04-2014
Publisher
Springer London
Published in
Osteoporosis International / Issue 4/2014
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-013-2577-1

Other articles of this Issue 4/2014

Osteoporosis International 4/2014 Go to the issue

Original Article

Factors associated with bisphosphonate treatment failure in postmenopausal women with primary osteoporosis

Original Article

Effects of age and starting age upon side asymmetry in the arms of veteran tennis players: a cross-sectional study

Letter

Periostin and its emerging role in systemic carcinogenesis

Original Article

Estrogen increases the transcription of human α2-Heremans-Schmid-glycoprotein by an interplay of estrogen receptor α and activator protein-1

Original Article

One-leg standing time and hip-fracture prediction

Original Article

Socioeconomic status in relation to incident fracture risk in the Study of Women’s Health Across the Nation