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01-03-2007 | Original Article

Identification of novel RANK polymorphisms and their putative association with low BMD among postmenopausal women

Authors: J.-M. Koh, B. L. Park, D. J. Kim, G. S. Kim, H. S. Cheong, T.-H. Kim, J.-M. Hong, H.-I. Shin, E. K. Park, S.-Y. Kim, H. D. Shin

Published in: Osteoporosis International | Issue 3/2007

Abstract

Introduction

Bone mineral density (BMD) is the major factor for determining bone strength, which is closely correlated to osteoporotic fracture risk and is largely determined by multiple genetic factors. The RANK (TNFRSF11A), receptor for RANKL, is a member of the tumor necrosis factor receptor (TNFR) superfamily and plays a central role in osteoclast development.

Methods

In order to investigate the effects of RANK polymorphism on BMD and osteoporosis, we directly sequenced the RANK gene in 24 Korean individuals and identified 25 sequence variants. Eleven of these polymorphisms were selected and genotyped in a larger-scale study of postmenopausal women (n = 560). Areal BMD (g/cm²) of the anterior–posterior lumbar spine and the nondominant proximal femur were measured using dual-energy X-ray absorptiometry.

Results

We found that two intronic polymorphisms in the RANK gene [RANK + 34863G > A (rs12458117) and RANK + 35928insdelC (new polymorphism found in this study) in intron 6] were significantly associated with the BMD of the lumbar spine, i.e., rare alleles were significantly associated with low BMD of the lumbar spine among Korean postmenopausal women (p = 0.04 and 0.02, respectively). These polymorphisms were also associated with low BMD of proximal femur sites, including Ward’s triangle, trochanter, and total femur. Our results suggest that +34863G > A and +35928insdelC polymorphisms in RANK are possible genetic factors for low BMD in postmenopausal women.

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NIH Consensus Development Panel on Osteoporosis Prevention D, and Therapy (2001) Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785–795CrossRef

Arden NK, Spector TD (1997) Genetic influences on muscle strength, lean body mass, and bone mineral density: a twin study. J Bone Miner Res 12:2076–2081PubMedCrossRef

Eisman JA (1999) Genetics of osteoporosis. Endocr Rev 20:788–804PubMedCrossRef

Kanis JA, Melton LJ 3rd, Christiansen C, Johnston CC, Khaltaev N (1994) The diagnosis of osteoporosis. J Bone Miner Res 9:1137–1141PubMed

Baron R (2004) Arming the osteoclast. Nat Med 10:458–460PubMedCrossRef

Biswas RN, Baker DN, Hruska KN, Chellaiah MN (2004) Polyphosphoinositides-dependent regulation of the osteoclast actin cytoskeleton and bone resorption. BMC Cell Biol 5:19PubMedCrossRef

Karst M, Gorny G, Galvin RJ, Oursler MJ (2004) Roles of stromal cell RANKL, OPG, and M-CSF expression in biphasic TGF-beta regulation of osteoclast differentiation. J Cell Physiol 200:99–106PubMedCrossRef

Teitelbaum SL (2000) Bone resorption by osteoclasts. Science 289:1504–1508PubMedCrossRef

Fata JE, Kong YY, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, Elliott R, Scully S, Voura EB, Lacey DL, Boyle WJ, Khokha R, Penninger JM (2000) The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103:41–50PubMedCrossRef

10.

Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, Tan HL, Elliott G, Kelley MJ, Sarosi I, Wang L, Xia XZ, Elliott R, Chiu L, Black T, Scully S, Capparelli C, Morony S, Shimamoto G, Bass MB, Boyle WJ (1999) Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 96:3540–3545PubMedCrossRef

11.

Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS 3rd, Frankel WN, Lee SY, Choi Y (1997) TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem 272:25190–25194PubMedCrossRef

12.

Galibert L, Tometsko ME, Anderson DM, Cosman D, Dougall WC (1998) The involvement of multiple tumor necrosis factor receptor (TNFR)- associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily. J Biol Chem 273:34120–34127PubMedCrossRef

13.

Darnay BG, Haridas V, Ni J, Moore PA, Aggarwal BB (1998) Characterization of the intracellular domain of receptor activator of NF-kappaB (RANK). Interaction with tumor necrosis factor receptor- associated factors and activation of NF-kappab and c-Jun N-terminal kinase. J Biol Chem 273:20551–20555PubMedCrossRef

14.

Yamamoto A, Miyazaki T, Kadono Y, Takayanagi H, Miura T, Nishina H, Katada T, Wakabayashi K, Oda H, Nakamura K, Tanaka S (2002) Possible involvement of IkappaB kinase 2 and MKK7 in osteoclastogenesis induced by receptor activator of nuclear factor kappaB ligand. J Bone Miner Res 17:612–621PubMedCrossRef

15.

Darnay BG, Ni J, Moore PA, Aggarwal BB (1999) Activation of NF-kappaB by RANK requires tumor necrosis factor receptor- associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif. J Biol Chem 274:7724–7731PubMedCrossRef

16.

Zhang DE, Hetherington CJ, Chen HM, Tenen DG (1994) The macrophage transcription factor PU.1 directs tissue-specific expression of the macrophage colony-stimulating factor receptor. Mol Cell Biol 14:373–381PubMed

17.

Johnson-Pais TL, Singer FR, Bone HG, McMurray CT, Hansen MF, Leach RJ (2003) Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis. J Bone Miner Res 18:376–380PubMedCrossRef

18.

Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H, Wallace RG, van Hul W, Whyte MP, Nakatsuka K, Hovy L, Anderson DM (2000) Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet 24:45–48PubMedCrossRef

19.

Cody JD, Singer FR, Roodman GD, Otterund B, Lewis TB, Leppert M, Leach RJ (1997) Genetic linkage of Paget disease of the bone to chromosome 18q. Am J Hum Genet 61:1117–1122PubMedCrossRef

20.

Good DA, Busfield F, Fletcher BH, Duffy DL, Kesting JB, Andersen J, Shaw JT (2002) Linkage of Paget disease of bone to a novel region on human chromosome 18q23. Am J Hum Genet 70:517–525PubMedCrossRef

21.

Choi JY, Shin A, Park SK, Chung HW, Cho SI, Shin CS, Kim H, Lee KM, Lee KH, Kang C, Cho DY, Kang D (2005) Genetic polymorphisms of OPG, RANK, and ESR1 and bone mineral density in Korean postmenopausal women. Calcif Tissue Int 77:152–159PubMedCrossRef

22.

Hsu YH, Niu T, Terwedow HA, Xu X, Feng Y, Li Z, Brain JD, Rosen CJ, Laird N, Xu X (2006) Variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are associated with bone mineral density at different skeletal sites in men. Hum Genet 118:568–577PubMedCrossRef

23.

Nathan H (1962) Osteophytes of the vertebral column: an anatomical study of their development according to age, race, and sex with considerations as to their etiology and significance. J Bone Joint Surg Am 44A:243–268

24.

Kiel D (1995) Assessing vertebral fractures. National Osteoporosis Foundation Working Group on Vertebral Fractures. J Bone Miner Res 10:518–523PubMedCrossRef

25.

Livak KJ (1999) Allelic discrimination using fluorogenic probes and the 5’ nuclease assay. Genet Anal 14:143–149PubMed

26.

Hedrick PW (1987) Gametic disequilibrium measures: proceed with caution. Genetics 117:331–341PubMed

27.

Hedrick P, Kumar S (2001) Mutation and linkage disequilibrium in human mtDNA. Eur J Hum Genet 9:969–972PubMedCrossRef

28.

Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989PubMedCrossRef

29.

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 11:306–311PubMedCrossRef

30.

Yamada Y, Miyauchi A, Takagi Y, Tanaka M, Mizuno M, Harada A (2001) Association of the C-509-> T polymorphism, alone of in combination with the T869-> C polymorphism, of the transforming growth factor-beta1 gene with bone mineral density and genetic susceptibility to osteoporosis in Japanese women. J Mol Med 79:149–156PubMedCrossRef

31.

Keen RW, Woodford-Richens KL, Lanchbury JS, Spector TD (1998) Allelic variation at the interleukin-1 receptor antagonist gene is associated with early postmenopausal bone loss at the spine. Bone 23:367–371PubMedCrossRef

32.

Murray RE, McGuigan F, Grant SF, Reid DM, Ralston SH (1997) Polymorphisms of the interleukin-6 gene are associated with bone mineral density. Bone 21:89–92PubMedCrossRef

33.

Garcia-Giralt N, Nogues X, Enjuanes A, Puig J, Mellibovsky L, Bay-Jensen A, Carreras R, Balcells S, Diez-Perez A, Grinberg D (2002) Two new single-nucleotide polymorphisms in the COL1A1 upstream regulatory region and their relationship to bone mineral density. J Bone Miner Res 17:384–393PubMedCrossRef

34.

Arko B, Prezelj J, Komel R, Kocijancic A, Hudler P, Marc J (2002) Sequence variations in the osteoprotegerin gene promoter in patients with postmenopausal osteoporosis. J Clin Endocrinol Metab 87:4080–4084PubMedCrossRef

35.

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 89:6665–6669PubMedCrossRef

36.

Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA (1994) Prediction of bone density from vitamin D receptor alleles. Nature 367:284–287PubMedCrossRef

37.

Kim GS, Koh JM, Chang JS, Park BL, Kim LH, Park EK, Kim SY, Shin HD (2005) Association of the OSCAR promoter polymorphism with BMD in postmenopausal women. J Bone Miner Res 20:1342–1348PubMedCrossRef

38.

Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342PubMedCrossRef

39.

Bachmann MF, Wong BR, Josien R, Steinman RM, Oxenius A, Choi Y (1999) TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation. J Exp Med 189:1025–1031PubMedCrossRef

40.

Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L (1997) A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390:175–179PubMedCrossRef

41.

Yan T, Riggs BL, Boyle WJ, Khosla S (2001) Regulation of osteoclastogenesis and RANK expression by TGF-beta1. J Cell Biochem 83:320–325PubMedCrossRef

42.

Arai F, Miyamoto T, Ohneda O, Inada T, Sudo T, Brasel K, Miyata T, Anderson DM, Suda T (1999) Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappaB (RANK) receptors. J Exp Med 190:1741–1754PubMedCrossRef

43.

Kido S, Inoue D, Iliura K, Javier W, Ito Y, Matsumoto T (2003) Expression of RANK is dependent upon differentiation into the macrophage/osteoclast lineage: induction by 1alpha, 25-dihydroxyvitamin D3 and TPA in a human myelomonocytic cell line, HL60. Bone 32:621–629PubMedCrossRef

44.

Kang HS, Park EK, Kim KH, Park JY, Choi JY, Shin HI, Jun CD, Kang SS, Kim SY (2004) Receptor activator of nuclear factor-kappaB is induced by a rottlerin-sensitive and p38 MAP kinase-dependent pathway during monocyte differentiation. Mol Cells 17(3):438–445PubMed

45.

Ast G (2004) How did alternative splicing evolve? Nat Rev Genet 5:773–782PubMedCrossRef

46.

MacGregor A, Snieder H, Spector TD (2000) Genetic factors and osteoporotic fractures in elderly people. Twin data support genetic contribution to risk of fracture. BMJ 320:1669–1670; author reply 1670–1661PubMedCrossRef

47.

Deng HW, Chen WM, Recker S, Stegman MR, Li JL, Davies KM, Zhou Y, Deng H, Heaney R, Recker RR (2000) Genetic determination of Colles’ fracture and differential bone mass in women with and without Colles’ fracture. J Bone Miner Res 15:1243–1252PubMedCrossRef

Title: Identification of novel RANK polymorphisms and their putative association with low BMD among postmenopausal women
Authors: J.-M. Koh
B. L. Park
D. J. Kim
G. S. Kim
H. S. Cheong
T.-H. Kim
J.-M. Hong
H.-I. Shin
E. K. Park
S.-Y. Kim
H. D. Shin
Publication date: 01-03-2007
Publisher: Springer-Verlag
Published in: Osteoporosis International / Issue 3/2007
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-006-0244-5

At a glance: The STEP trials

Springer Medicine

Identification of novel RANK polymorphisms and their putative association with low BMD among postmenopausal women

Abstract

Introduction

Methods

Results

At a glance: The STEP trials

Springer Medicine

Abstract

Introduction

Methods

Results

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