Calcified Tissue International

, Volume 81, Issue 4, pp 254–262

Variation in the BMP2 Gene: Bone Mineral Density and Ultrasound in Young Adult and Elderly Women

  • Fiona E. McGuigan
  • Emma Larzenius
  • Mattias Callreus
  • Paul Gerdhem
  • Holger Luthman
  • Kristina Åkesson


Bone morphogenetic protein-2 (BMP2) plays a key role in bone formation and maintenance. Studies of polymorphisms within the gene in relation to bone mineral density (BMD) and fracture have been inconsistent. Our aim was to investigate associations between polymorphisms in the BMP2 gene and bone mass, fracture, and quantitative ultrasound (QUS) measures at different stages of skeletal development. Study subjects were participants of two population-based cohorts of Swedish women: the PEAK-25 cohort of young adult women aged 25 years (n = 993) and the OPRA cohort of elderly women aged 75 years (n = 1,001). We analyzed four single-nucleotide polymorphisms (SNPs) across the BMP2 gene including the Ser37Ala SNP previously identified in relation to BMD, QUS of the calcaneus, and, in the elderly women, fracture. BMP2 gene variations were associated with QUS of bone, independent of BMD, but only in the young women. Even after adjusting for confounding factors, SNP rs235754 in the 3′ region of the gene was significantly associated with the ultrasound parameters speed of sound (P = 0.003) and stiffness (P = 0.002). The 5′ SNP rs235710 showed trends for QUS parameters (P = 0.02–0.07). No association with BMP2 SNPs was observed in either cohort for either BMD or fracture. While further, more extensive genotyping across the gene is recommended, as we may not have captured all information, our preliminary data suggest that variation in BMP2 may play a previously unidentified role in aspects of bone quality, which may be age- and site-dependent.


BMP2 Polymorphism Peak bone mass Ultrasound Fracture 


  1. 1.
    Andrew T, Antioniades L, Scurrah KJ, Macgregor AJ, Spector TD (2005) Risk of wrist fracture in women is heritable and is influenced by genes that are largely independent of those influencing BMD. J Bone Miner Res 20:67–74PubMedCrossRefGoogle Scholar
  2. 2.
    Howard GM, Nguyen TV, Harris M, Kelly PJ, Eisman JA (1998) Genetic and environmental contributions to the association between quantitative ultrasound and bone mineral density measurements: a twin study. J Bone Miner Res 13:1318–1327PubMedCrossRefGoogle Scholar
  3. 3.
    Gluer CC, Cummings SR, Bauer DC, Stone K, Pressman A, Mathur A, Genant HK (1996) Osteoporosis: association of recent fractures with quantitative US findings. Radiology 199:725–732PubMedGoogle Scholar
  4. 4.
    Arden NK, Baker J, Hogg C, Baan K, Spector TD (1996) The heritability of bone mineral density, ultrasound of the calcaneus and hip axis length: a study of postmenopausal twins. J Bone Miner Res 11:530–534PubMedGoogle Scholar
  5. 5.
    Grant SF, Reid DM, Blake G, Herd R, Fogelman I, Ralston SH (1996) Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene. Nat Genet 14:203–205PubMedCrossRefGoogle Scholar
  6. 6.
    Gerdhem P, Brandstrom H, Stiger F, Obrant K, Melhus H, Ljunggren O, Kindmark A, Akesson K (2004) Association of the collagen type 1 (COL1A 1) Sp1 binding site polymorphism to femoral neck bone mineral density and wrist fracture in 1,044 elderly Swedish women. Calcif Tissue Int 74:264–269PubMedCrossRefGoogle Scholar
  7. 7.
    Kobayashi S, Inoue S, Hosoi T, Ouchi Y, Shiraki M, Orimo H (1996) Association of bone mineral density with polymorphism of the estrogen receptor gene. J Bone Miner Res 11:306–311PubMedCrossRefGoogle Scholar
  8. 8.
    Ioannidis JP, Ralston SH, Bennett ST, Brandi ML, Grinberg D, Karassa FB, Langdahl B, van Meurs JB, Mosekilde L, Scollen S, Albagha OM, Bustamante M, Carey AH, Dunning AM, Enjuanes A, van Leeuwen JP, Mavilia C, Masi L, McGuigan FE, Nogues X, Pols HA, Reid DM, Schuit SC, Sherlock RE, Uitterlinden AG (2004) Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. JAMA 292:2105–2114PubMedCrossRefGoogle Scholar
  9. 9.
    Morrison NA, Yeoman R, Kelly PJ, Eisman JA (1992) Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphism and circulating osteocalcin. Proc Natl Acad Sci USA 89:6665–6669PubMedCrossRefGoogle Scholar
  10. 10.
    Fang Y, van Meurs JB, d’Alesio A, Jhamai M, Zhao H, Rivadeneira F, Hofman A, van Leeuwen JP, Jehan F, Pols HA, Uitterlinden AG (2005) Promoter and 3’–untranslated–region haplotypes in the vitamin D receptor gene predispose to osteoporotic fracture: the Rotterdam Study. Am J Hum Genet 77:807–823PubMedCrossRefGoogle Scholar
  11. 11.
    Macdonald HM, McGuigan FE, Stewart A, Black AJ, Fraser WD, Ralston S, Reid DM (2006) Large-scale population–based study shows no evidence of association between common polymorphism of the VDR gene and BMD in British women. J Bone Miner Res 21:151–162PubMedCrossRefGoogle Scholar
  12. 12.
    Yamada Y, Miyauchi A, Goto J, Takagi Y, Okuizumi H, Kanematsu M, Hase M, Takai H, Harada A, Ikeda K (1998) Association of a polymorphism of the transforming growth factor-beta1 gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women. J Bone Miner Res 13:1569–1576PubMedCrossRefGoogle Scholar
  13. 13.
    McGuigan FE, Macdonald HM, Bassiti A, Farmer R, Bear S, Stewart A, Black A, Fraser WD, Welsh F, Reid DM, Ralston SH (2007) Large–scale population–based study shows no association between common polymorphisms of the TGFB1 gene and BMD in women. J Bone Miner Res 22:195–202PubMedCrossRefGoogle Scholar
  14. 14.
    Thies RS, Bauduy M, Ashton BA, Kurtzberg L, Wozney JM, Rosen V (1992) Recombinant human bone morphogenetic protein–2 induces osteoblastic differentiation in W-20–17 stromal cells. Endocrinology 130:1318–1324PubMedCrossRefGoogle Scholar
  15. 15.
    Miyazono K (2000) TGF-beta signaling by Smad proteins. Cytokine Growth Factor Rev 11:15–22PubMedCrossRefGoogle Scholar
  16. 16.
    Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, Bjarnadottir E, Johannsdottir VD, Sigurdardottir MS, Bagger Y, Christiansen C, Reynisdottir I, Grant SF, Jonasson K, Frigge ML, Gulcher JR, Sigurdsson G, Stefansson K (2003) Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS Biol 1:E69PubMedCrossRefGoogle Scholar
  17. 17.
    Choi JY, Shin CS, Hong YC, Kang D (2006) Single-nucleotide polymorphisms and haplotypes of bone morphogenetic protein genes and peripheral bone mineral density in young Korean men and women. Calcif Tissue Int 78:203–211PubMedCrossRefGoogle Scholar
  18. 18.
    Ichikawa S, Johnson ML, Koller DL, Lai D, Xuei X, Edenberg HJ, Hui SL, Foroud TM, Peacock M, Econs MJ (2006) Polymorphisms in the bone morphogenetic protein 2 (BMP2) gene do not affect bone mineral density in white men or women. Osteoporos Int 17:587–592PubMedCrossRefGoogle Scholar
  19. 19.
    Medici M, van Meurs JB, Rivadeneira F, Zhao H, Arp PP, Hofman A, Pols HA, Uitterlinden AG (2006) BMP-2 gene polymorphisms and osteoporosis: the Rotterdam Study. J Bone Miner Res 21:845–854PubMedCrossRefGoogle Scholar
  20. 20.
    Reneland RH, Mah S, Kammerer S, Hoyal CR, Marnellos G, Wilson SG, Sambrook PN, Spector TD, Nelson MR, Braun A (2005) Association between a variation in the phosphodiesterase 4D gene and bone mineral density. BMC Med Genet 6:9PubMedCrossRefGoogle Scholar
  21. 21.
    Okamoto M, Murai J, Yoshikawa H, Tsumaki N (2006) Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development. J Bone Miner Res 21:1022–1033PubMedCrossRefGoogle Scholar
  22. 22.
    Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989PubMedCrossRefGoogle Scholar
  23. 23.
    Stewart TL, Jin H, McGuigan FE, Albagha OM, Garcia-Giralt N, Bassiti A, Grinberg D, Balcells S, Reid DM, Ralston SH (2006) Haplotypes defined by promoter and intron 1 polymorphisms of the COLIA1 gene regulate bone mineral density in women. J Clin Endocrinol Metab 91:3575–3583PubMedCrossRefGoogle Scholar
  24. 24.
    Yamaguchi A, Katagiri T, Ikeda T, Wozney JM, Rosen V, Wang EA, Kahn AJ, Suda T, Yoshiki S (1991) Recombinant human bone morphogenetic protein–2 stimulates osteoblastic maturation and inhibits myogenic differentiation in vitro. J Cell Biol 113:681–687PubMedCrossRefGoogle Scholar
  25. 25.
    Yoon BS, Lyons KM (2004) Multiple functions of BMPs in chondrogenesis. J Cell Biochem 93:93–103PubMedCrossRefGoogle Scholar
  26. 26.
    Burkus JK, Gornet MF, Dickman CA, Zdeblick TA (2002) Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages. J Spinal Disord Tech 15:337–349PubMedGoogle Scholar
  27. 27.
    Einhorn TA, Majeska RJ, Mohaideen A, Kagel EM, Bouxsein ML, Turek TJ, Wozney JM (2003) A single percutaneous injection of recombinant human bone morphogenetic protein–2 accelerates fracture repair. J Bone Joint Surg Am 85:1425–1435PubMedGoogle Scholar
  28. 28.
    Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, Aro H, Atar D, Bishay M, Borner MG, Chiron P, Choong P, Cinats J, Courtenay B, Feibel R, Geulette B, Gravel C, Haas N, Raschke M, Hammacher E, van der Velde D, Hardy P, Holt M, Josten C, Ketterl RL, Lindeque B, Lob G, Mathevon H, McCoy G, Marsh D, Miller R, Munting E, Oevre S, Nordsletten L, Patel A, Pohl A, Rennie W, Reynders P, Rommens PM, Rondia J, Rossouw WC, Daneel PJ, Ruff S, Ruter A, Santavirta S, Schildhauer TA, Gekle C, Schnettler R, Segal D, Seiler H, Snowdowne RB, Stapert J, Taglang G, Verdonk R, Vogels L, Weckbach A, Wentzensen A, Wisniewski T (2002) Recombinant human bone morphogenetic protein–2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am 84:2123–2134PubMedCrossRefGoogle Scholar
  29. 29.
    Murnaghan M, McIlmurray L, Mushipe MT, Li G (2005) Time for treating bone fracture using rhBMP-2: a randomised placebo controlled mouse fracture trial. J Orthop Res 23:625–631PubMedCrossRefGoogle Scholar
  30. 30.
    Schmidmaier G, Lucke M, Schwabe P, Raschke M, Haas NP, Wildemann B (2006) Collective review. Bioactive implants coated with poly(d,l-lactide) and growth factors IGF-I, TGF-beta1, or BMP-2 for stimulation of fracture healing. J Long Term Eff Med Implants 16:61–69PubMedGoogle Scholar
  31. 31.
    Tsuji K, Bandyopadhyay A, Harfe BD, Cox K, Kakar S, Gerstenfeld L, Einhorn T, Tabin CJ, Rosen V (2006) BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat Genet 38(12):1424–1429PubMedCrossRefGoogle Scholar
  32. 32.
    Zimmermann G, Henle P, Kusswetter M, Moghaddam A, Wentzensen A, Richter W, Weiss S (2005) TGF-beta1 as a marker of delayed fracture healing. Bone 36:779–785PubMedCrossRefGoogle Scholar
  33. 33.
    Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29:306–309PubMedCrossRefGoogle Scholar
  34. 34.
    Beamer WG, Donahue LR, Rosen CJ, Baylink DJ (1996) Genetic variability in adult bone density among inbred strains of mice. Bone 18:397–403PubMedCrossRefGoogle Scholar
  35. 35.
    Albagha OM, McGuigan FE, Reid DM, Ralston SH (2001) Estrogen receptor alpha gene polymorphisms and bone mineral density: haplotype analysis in women from the United Kingdom. J Bone Miner Res 16:128–134PubMedCrossRefGoogle Scholar
  36. 36.
    Chung HW, Seo JS, Hur SE, Kim HL, Kim JY, Jung JH, Kim LH, Park BL, Shin HD (2003) Association of interleukin-6 promoter variant with bone mineral density in pre–menopausal women. J Hum Genet 48:243–248PubMedCrossRefGoogle Scholar
  37. 37.
    Langdahl BL, Carstens M, Stenkjaer L, Eriksen EF (2003) Polymorphisms in the transforming growth factor beta 1 gene and osteoporosis. Bone 32:297–310PubMedCrossRefGoogle Scholar
  38. 38.
    Nordstrom A, Gerdhem P, Brandstrom H, Stiger F, Lerner UH, Lorentzon M, Obrant K, Nordstrom P, Akesson K (2004) Interleukin-6 promoter polymorphism is associated with bone quality assessed by calcaneus ultrasound and previous fractures in a cohort of 75-year-old women. Osteoporos Int 15:820–826PubMedCrossRefGoogle Scholar
  39. 39.
    Tzakas P, Wong BY, Logan AG, Rubin LA, Cole DE (2005) Transforming growth factor beta-1 (TGFB1) and peak bone mass: association between intragenic polymorphisms and quantitative ultrasound of the heel. BMC Musculoskelet Disord 6:29PubMedCrossRefGoogle Scholar
  40. 40.
    Zajickova K, Zofkova I, Hill M (2005) Vitamin D receptor polymorphisms, bone ultrasound and mineral density in post-menopausal women. Aging Clin Exp Res 17:121–124PubMedGoogle Scholar
  41. 41.
    Duncan EL, Cardon LR, Sinsheimer JS, Wass JA, Brown MA (2003) Site and gender specificity of inheritance of bone mineral density. J Bone Miner Res 18:1531–1538PubMedCrossRefGoogle Scholar
  42. 42.
    Judex S, Garman R, Squire M, Donahue LR, Rubin C (2004) Genetically based influences on the site-specific regulation of trabecular and cortical bone morphology. J Bone Miner Res 19:600–606PubMedCrossRefGoogle Scholar
  43. 43.
    Ralston SH, Galwey N, MacKay I, Albagha OM, Cardon L, Compston JE, Cooper C, Duncan E, Keen R, Langdahl B, McLellan A, O’Riordan J, Pols HA, Reid DM, Uitterlinden AG, Wass J, Bennett ST (2005) Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study. Hum Mol Genet 14:943–951PubMedCrossRefGoogle Scholar
  44. 44.
    Turner CH, Roeder RK, Wieczorek A, Foroud T, Liu G, Peacock M (2001) Variability in skeletal mass, structure, and biomechanical properties among inbred strains of rats. J Bone Miner Res 16:1532–1539PubMedCrossRefGoogle Scholar
  45. 45.
    Kakoki M, Tsai YS, Kim HS, Hatada S, Ciavatta DJ, Takahashi N, Arnold LW, Maeda N, Smithies O (2004) Altering the expression in mice of genes by modifying their 3’ regions. Dev Cell 6:597–606PubMedCrossRefGoogle Scholar
  46. 46.
    Fritz DT, Jiang S, Xu J, Rogers MB (2006) A polymorphism in a conserved posttranscriptional regulatory motif alters bone morphogenetic protein 2 (BMP2) RNA:protein interactions. Mol Endocrinol 20:1574–1586PubMedCrossRefGoogle Scholar
  47. 47.
    Yamamoto T, Saatcioglu F, Matsuda T (2002) Cross-talk between bone morphogenic proteins and estrogen receptor signaling. Endocrinology 143:2635–2642PubMedCrossRefGoogle Scholar
  48. 48.
    Zhou S, Turgeman G, Harris SE, Leitman DC, Komm BS, Bodine PV, Gazit D (2003) Estrogens activate bone morphogenetic protein-2 gene transcription in mouse mesenchymal stem cells. Mol Endocrinol 17:56–66PubMedCrossRefGoogle Scholar
  49. 49.
    Xiong DH, Shen H, Zhao LJ, Xiao P, Yang TL, Guo Y, Wang W, Guo YF, Liu YJ, Recker RR, Deng HW (2006) Robust and comprehensive analysis of 20 osteoporosis candidate genes by very high-density single-nucleotide polymorphism screen among 405 white nuclear families identified significant association and gene–gene interaction. J Bone Miner Res 21:1678–1695PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Fiona E. McGuigan
    • 1
    • 2
  • Emma Larzenius
    • 1
    • 2
  • Mattias Callreus
    • 1
    • 2
  • Paul Gerdhem
    • 1
    • 4
  • Holger Luthman
    • 3
    • 5
  • Kristina Åkesson
    • 1
    • 2
  1. 1.Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences MalmöLund UniversityMalmöSweden
  2. 2.Department of OrthopedicsMalmö University HospitalMalmöSweden
  3. 3.Medical Genetics Unit, Department of Clinical Sciences MalmöLund UniversityMalmöSweden
  4. 4.Department of OrthopedicsKarolinska University Hospital, Karolinska InstituteStockholmSweden
  5. 5.Clinical Research CenterMalmö University HospitalMalmöSweden

Personalised recommendations