Association of transforming growth factor (TGF) p1 T(861-20)C polymorphism with bone mineral density and TGFip gene expression in postmenopausal osteoporosis

Objective: to study the mechanism for the involvement of ТGFβ1 T(861-20)C in bone resorption in postmenopausal osteoporosis (OP). Material and methods. DNA from 158 postmenopausal women and patients with OP and from 89 healthy age-matched women was examined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (PCR-RFLP) analysis. Bone mineral density (BMD) was estimated by dual-energy X-ray absorptiometry. Standard biochemical protocols were used to detect alkaline phosphatase activity and calcium and phosphorus levels in serum. Total RNA was isolated from the peripheral blood of 32 patients with OP and 39 healthy donors and used for real-time PCR study. Results. No significant differences were found in the frequency of individual alleles and genotypes between the OP group and control donors. The minor T allele frequency was 0.27. There was a significant correlation of ТGFβ1 T(861-20)C polymorphism with low lumbar spine BMD (r=0.18; p=0.025) in Russian patients with OP. Age-adjusted (Z-score) BMD in CC genotype carriers turned to be significantly lower than that in CT and TT genotype carriers. This was accompanied by lower ТGFβ1 gene expression in the peripheral blood of CC genotype carriers (n=10) as compared to the combined group of carriers of two other genotypes (n=22) in the OP group (p=0.03). No changes in ТGFβ1 gene expression were seen in healthy women who were CC genotype carriers (n=18) as compared to the combined representatives of two other genotypes (n=21). Overall, the OP group exhibited significantly lower ТGFβ1 gene expression than the healthy controls (p=0.04). Conclusion. The association of ТGFβ1 (861-20)CC genotype with lower lumbar spine BMD in patients with OP is attended by decreased ТGFβ1 gene expression. Therefore, ТGFβ1 T(861-20)C polymorphism may be a predictor for the development of OP and the more severe form of the disease may be expected in (861-20)CC genotype carriers.

postmenopausal osteoporosis, bone mineral density, single nucleotide polymorphism, transforming growth factor β1, blood gene expression in blood

1. <div><p>World Health Organization Study Group. Assessment of fracture risk and its application for screening for postmenopausal osteoporosis. Geneva: WHO, 1994.</p><p>Colon-Emeric C.S., Saag K.G. Osteoporotic fractures in older adults. Best Pract Res Clin Rheumatol 2006;20:695-706.</p><p>Patel M.S., Rubin L.A, Cole D.E. Genetic determinants of peak bone mass. In: The osteoporosis Primer. Ed. by J.E. Henderson, D. Goltzman. Cambridge: Cambridge University Press, 2000;131 —46.</p><p>Kung A.W., Huang Q.Y. Genetic and environmental determinants of osteoporosis. J Musculoskelet Neuronal Interact 2007;7:26-32.</p><p>Heller H.A., Salzano F.M., Barrantes R. et al. Intra- and intercontinental molecular variability of an Alu insertion in the 3’ untranslated region of the LDLR gene. Hum Biol 2004;76:591-604.</p><p>Крылов М.Ю., Короткова Т.А., Мякоткин В.А., Беневоленская Л.И. Аллельные полиморфизмы щелочной фостатазы, растворимой кислой фосфатазы и витамин Д-связывающего белка при постменопаузальном остеопорозе. Тер арх 2004;5:61-6.</p><p>Тагиева А.Н., Сметник М.З., Сухих В.П., Крылов М.Ю. Функциональная роль полиморфизмов генов рецептора витамина Д, эстрогенового рецептора (ER) цепи альфа 1 коллагена I типа (COLIAI) при постменопаузальном остеопорозе. Мед ген 2005;4:90-5.</p><p>Battila J., Fagundes N.J., Heller A.H. et al. Alu insertion polymorphisms in Native Americans and related Asian populations. Ann Hum Biol 2006;33:142-60.</p><p>Мякоткин В.А., Крылов М.Ю., Казеева А.К. и др. Роль полиморфизмов генов LRP5, BMP4 и TGF1 при постменопаузальном остеопорозе. Науч-практич ревматол 2008;3:8-15.</p><p>Маслова К.А., Крылов М.Ю., Торопцова Н.В. и др. Полиморфизмы генов эстрогеновых рецепторов α и β при постменопаузальном остеопорозе. Науч-практич ревматол 2008;3:16-21.</p><p>Cohen M.M. Jr. TGF-beta/Smad signaling system and its pathologic correlates. Am J Med Genet A 2003;116:1-10.</p><p>Oreffo R.O.C., Mundy G.R., Seyedin S.M., Bonewald L.F. Activation of the bone-derived latent TGF0 complex by isolated osteoclasts. Biochem Biophys Res Commun 1989;158:817-23.</p><p>Oursler M.J. Osteoclast synthesis and secretion and activation of latent transforming growth factor β. J Bone Miner Res 1994;9:443-52.</p><p>Bonewald L.F. Transforming growth factor-β. In: Bilezikian J.P., Raisz L.G., Rodan G.A. (eds). Principles of Bone Biology. San Diego, CA, USA: Academic Press, 1996;647—59.</p><p>Noda M., Camilliere J.J. In vitro stimulation of bone formation by transforming growth factor-0. Endocrinology 1989;124:2991-4.</p><p>Pacifici R. Estrogen, cytokines, and pathogenesis of post menopausal osteoporosis. J Bone Miner Res 1996;11:1043-51.</p><p>Hughes D.E., Dai A., Tiffee J.C. et al. Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-0. Nat Med 1996;2:1132-6.</p><p>Ashcroft G.S., Dodsworth J., van Boxtel E. et al. Estrogen accelerates cutaneous wound healing associated with an increase in TGF01 levels. Nat Med 1997;3:1209-15.</p><p>Ongphiphadhanakul B., Chanprasertyothin S., Payattikul P. et al. Association of a G2014A transition in exon 8 of the estrogen receptor-β gene with postmenopausal osteoporosis. Osteoporosis Int 2001;12:1015-9.</p><p>Janssens K., ten Dijke P., Ralston S.H. et al. Transforming growth factor β1 mutations in Camurati-Endelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein. J Biol Chem 2003;278:7718-24.</p><p>Geiser A.G., Zeng Q.Q., Sato M. et al. Decreased bone mass and bone elasticity in mice lacking the transforming growth factor-β gene. Bone 1998;23:87-93.</p><p>Lindberg M.K., Moverare S., Eriksson A.-L. et al. Identification of estrogen-regulated genes of potential importance for the regulation of trabecular bone mineral density. J Bone Miner Res 2002;17:2183-95.</p><p>Yamada Y. Association of polymorphisms of the transforming growth factor-β1 gene with genetic susceptibility to osteoporosis. Pharmacogenetics 2001;11:765-71.</p><p>Lau H.H., Ho A.Y.Y., Luk K.D.K., Kung A.W.C. Transforming growth factor-β1 gene polymorphisms and bone turnover, bone mineral density and fracture risk in Southern Chinese women. Calcif Tissue Int 2004;74:516-21.</p><p>Langdahl B.L., Carstens M., Stenkjaer L., Eriksen E.F. Polymorphisms in the transforming growth factor-beta1 gene and osteoporosis. Bone 2003;32:297-310.</p><p>Benson S.A., Hall M.N., Silhavy T.J. Genetic analysis of protein export in Escherichia coli. Annu Rev Biochem 1985;54:101-34.</p><p>Verner K., Schatz G. Protein translocation across membranes. Science 1988;241:1307-13.</p><p>Keen R.W., Snieder H., Molloy H. et al. Evidence of association and linkage disequilibrium between a novel polymorphism in the transforming growth factor beta 1 gene and hip bone mineral density: a study of female twins. Rheumatology 2001;40:48-54.</p><p>Grainger D.J., Heathcote K., Chiano M. et al. Genetic control of the circulating concentrations of transforming growth factor-beta1. Hum Mol Genet 1999;8:93-7.</p><p>Hinke V., Seck T., Clanget C., Scheidt-Nave C. et al. Association of transforming growth factor-β1 (TGFβ1) T29→ C gene polymorphism with bone mineral density (BMD), changes in BMD, and serum concentrations of TGFβ1 in a population-based sample of postmenopausal German women. Calcif Tissue Int 2001;69:315-20.</p><p>Grainger D.J., Percival J., Chiano M., Spector T.D. The role of serum TGF-beta isoforms as potential markers of osteoporosis. Osteoporosis Int 1999;9:398-404.</p><p>Dick I.M., Devine A., Li S. et al. The T869C TGFbeta polymorphism is associated with fracture, bone mineral density, and calcaneal quantitative ultrasound in elderly women. Bone 2003;33:335-41.</p><p>Shah R., Hurley C.K., Posch P.E. A molecular mechanism for the differential regulation of TGF-beta1 expression due to the common SNP-509-T (C.-1347C&gt;T). Hum Genet 2006;120:461-9.</p><p>Mak Y.T., Hampson G., Beresford J.N., Spector T.D. Variations in genome-wide gene expression in identical twins - a study of primary osteoblast-like culture from female twins discordant for osteoporosis. BMC Genetics 2004;5:14-21.</p><p>Riancho J.A., Valero C., Naranjo A. et al. Identification of an apromatese haplotype that is associated with gene expression and postmenopausal osteoporosis. J Clin Endocrinol Metab 2006;92:660-5.</p><p>Miller S.A., Dykes D.D., Polesky H.F. A simple salting-out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res 1988;16:12-5.</p><p>Четина Е.В., ДиБаттиста Д., Пул А.Р. Роль простагландина Е2 в ингибировании разрушения коллагена суставного хряща больных остеоартрозом. Науч-практич ревматол 2009;3:18-24.</p><p>Tzakas P., Wong B.Y., Logan A.G. et al. Transforming growth factor beta-1 (TGFb1) and peak bone mass: Association between intragenic polymorphisms and quantitative ultrasound of the heel. BMC Musculoskelet Disord 2005;6:29-39.</p><p>Hering S., Jost C., Schulz H. et al. Circulating transforming growth factor-beta1 (TGFbeta1) is elevated by extensive exercise. Eur J Appl Physiol 2002;86:406-10.</p><p>Rosen C.J. Endocrine disorders and osteoporosis. Curr Opin Rheumatol 1997;9:355-61.</p><p>Garnero P. Biochemical markers of bone turnover: recent data and avenues for the future. Rev Rhum Engl Ed 1999;66:538-42.</p><p>Teitelbaum S.L. Postmenopausal osteoporosis, T cells, and immune dysfunction. Proc Natl Acad Sci USA 2004;101:16711-12.</p><p>Rifas L., Arackal S. T cells regulate the expression of matrix metalloproteinase in human osteoblasts via a dual mitogen-activated protein kinase mechanism. Arthr Rheum 2003;48:993-1001.</p><p>Xiao P., Chen Y., Jiang H. et al. In vivo genome-wide expression study on human circulating B cells suggest a novel ESR1 and MAPK3 network for postmenopausal osteoporosis. J Bone Miner Res 2008;23:644-54.</p><p>Finkelman R.D., Bell N.H., Strong D.D. et al. Ovariectomy selectively reduces the concentration of transforming growth factor beta in rat bone: implications for estrogen deficiency-associated bone loss. Proc Natl Acad Sci USA 1992;89:12190-3.</p><p>Ikeda T., Shigeno C., Kasai R. et al. Ovariectomy decreases the mRNA levels of transforming growth factor-beta 1 and increases the mRNA levels of osteocalcin in rat bone in vivo. Biochem Biophys Res Commun 1993;194:1228-33.</p></div><br />