Abstract
Wnt ligands are important regulators of skeletal homeostasis. Wnt10B tends to stimulate the differentiation of common mesenchymal precursors toward the osteoblastic lineage, while inhibiting adipocytic differentiation. Hence, we decided to explore the association of WNT10B allelic variants with bone mineral density and osteoporotic fractures. A set of tag SNPs capturing most common variations of the WNT10B gene was genotyped in 1438 Caucasian postmenopausal women, including 146 with vertebral fractures and 432 with hip fractures. We found no association between single SNPs and spine or hip bone mineral density (BMD). In the multilocus analysis, some haplotypes showed a slight association with spine BMD (P = 0.03), but it was not significant after multiple-test correction. There was no association between genotype and vertebral or hip fractures. Transcripts of WNT10B and other Wnt ligands were detected in human bone samples by real-time PCR. However, there was no relationship between genotype and RNA abundance. Thus, WNT10B is expressed in the bone microenvironment and may be an important regulator of osteoblastogenesis, but we have not found evidence for a robust association of common WNT10B gene allelic variants with either BMD or fractures in postmenopausal women.
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References
Ralston SH, de Crombrugghe B (2006) Genetic regulation of bone mass and susceptibility to osteoporosis. Genes Dev 20:2492–2506
Lei SF, Jiang H, Deng FY et al (2007) Searching for genes underlying susceptibility to osteoporotic fracture: current progress and future prospect. Osteoporos Int 18:1157–1175
Little RD, Carulli JP, Del Mastro RG et al (2002) A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 70:11–19
Glass DA, Karsenty G (2007) In vivo analysis of Wnt signaling in bone. Endocrinology 148:2630–2634
Krishnan V, Bryant HU, MacDougald OA (2006) Regulation of bone mass by Wnt signaling. J Clin Invest 116:1202–1209
Wang HY, Liu T, Malbon CC (2006) Structure-function analysis of Frizzleds. Cell Signal 18:934–941
Kikuchi A, Yamamoto H, Kishida S (2007) Multiplicity of the interactions of Wnt proteins and their receptors. Cell Signal 19:659–671
Bennett CN, Longo KA, Wright WS et al (2005) Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci USA 102:3324–3329
Zhou H, Mak W, Zheng Y et al (2008) Osteoblasts directly control lineage commitment of mesenchymal progenitor cells through Wnt signaling. J Biol Chem 283:1936–1945
Robinson JA, Chatterjee-Kishore M, Yaworsky PJ et al (2006) Wnt/beta-catenin signaling is a normal physiological response to mechanical loading in bone. J Biol Chem 281:31720–31728
Bonewald LF, Johnson ML (2008) Osteocytes, mechanosensing and Wnt signaling. Bone 42:606–615
Barrett JC, Fry B, Maller J et al (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265
Conde L, Vaquerizas JM, Dopazo H et al (2006) PupaSuite: finding functional single nucleotide polymorphisms for large-scale genotyping purposes. Nucleic Acids Res 34:W621–W625
Zmuda JM, Yerges LM, Kammerer CM et al (2009) Association analysis of WNT10B with bone mass and structure among individuals of African ancestry. J Bone Miner Res 24:437–447
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 25:402–408
Purcell S, Neale B, Todd-Brown K et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575
Neale BM, Ferreira MAR, Medland SE, Posthuma D (2007) Statistical genetics: gene mapping through linkage and association. Taylor and Francis, London
Gauderman WJ (2002) Sample size requirements for association studies of gene-gene interaction. Am J Epidemiol 155:478–484
Ugur SA, Tolun A (2008) Homozygous WNT10b mutation and complex inheritance in split-hand/foot malformation. Hum Mol Genet 17:2644–2653
Nishizuka M, Koyanagi A, Osada S et al (2008) Wnt4 and Wnt5a promote adipocyte differentiation. FEBS Lett 582:3201–3205
Kang S, Bennett CN, Gerin I et al (2007) Wnt signaling stimulates osteoblastogenesis of mesenchymal precursors by suppressing CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma. J Biol Chem 282:14515–14524
Bennett CN, Ouyang H, Ma YL et al (2007) Wnt10b increases postnatal bone formation by enhancing osteoblast differentiation. J Bone Miner Res 22:1924–1932
Liu J, Zou L, Wang J et al (2009) Hydrostatic pressure promotes Wnt10b and Wnt4 expression dependent and independent on ERK signaling in early-osteoinduced MSCs. Biochem Biophys Res Commun 379:505–509
Acknowledgments
This work was supported by FIS Grants 06/0034 and 05/0125. We thank the staff at the Centro Nacional de Genotipado, particularly Maria Torres, for their help with genotyping.
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Perez-Castrillon, J.L., Olmos, J.M., Nan, D.N. et al. Polymorphisms of the WNT10B Gene, Bone Mineral Density, and Fractures in Postmenopausal Women. Calcif Tissue Int 85, 113–118 (2009). https://doi.org/10.1007/s00223-009-9256-4
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DOI: https://doi.org/10.1007/s00223-009-9256-4