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Klotho Gene Polymorphism and Male Bone Mass

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Abstract

The Klotho gene codes for a protein that is thought to influence the homeostasis of several tissues, including bone, as well as the aging process. Although the mechanism of action has not been fully elucidated, some studies in women have associated Klotho allelic variants to bone mineral density (BMD). The objective of this study was to determine the relationship of a common T/G polymorphism, resulting in a phenylalanine (F) to valine (V) substitution, with male bone mass. BMD was measured by dual-energy X-ray absorptiometry in 362 Spanish men aged 19–83 years. Klotho alleles were determined by a Taqman assay. Allele frequencies were 85% and 15% for the F and V alleles, respectively. In comparison with the most common FF genotype, young and middle-aged men (age less than 53 years) with FV/VV genotypes had higher age- and body mass index-adjusted BMD at the lumbar spine (1.059 ± 0.017 vs. 1.016 ± 0.011 g/cm2, P = 0.036), the hip (1.077 ± 0.017 vs. 1.033 ± 0.011 g/cm2, P = 0.028), and the calcaneus (0.599 ± 0.125 vs. 0.547 ± 0.108 g/cm2, P = 0.012). Klotho alleles explained about 2–4% of BMD variance. However, Klotho genotype was not associated to BMD in older men. There were no Klotho-related differences in height, body weight, calcium intake, tobacco or alcohol consumption, or serum testosterone levels. In conclusion, these results suggest that allelic variants of Klotho constitute one of the genetic factors influencing BMD in male adults.

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References

  1. Ralston SH (2002) Genetic control of susceptibility to osteoporosis. J Clin Endocrinol Metab 87:2460–2466

    Article  PubMed  CAS  Google Scholar 

  2. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa A, Nagai R, Nabeshima Y (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51

    Article  PubMed  CAS  Google Scholar 

  3. Arking DE, Krebsova A, Macek M, Macek M, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC (2002) Association of human aging with a functional variant of klotho. Proc Natl Acad Sci USA 99:856–861

    Article  PubMed  CAS  Google Scholar 

  4. Arking DE, Atzmon G, Arking A, Barzilai N, Dietz HC (2005) Association between a functional variant of the Klotho gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ Res 96:412–418

    Article  PubMed  CAS  Google Scholar 

  5. Hamerman D (2005) Osteoporosis and atherosclerosis: biological linkages and the emergence of dual-purpose therapies. QJM 98:467–484

    Article  PubMed  CAS  Google Scholar 

  6. Jorgensen L, Joakimsen O, Rosvold Berntsen GK, Heuch I, Jacobsen BK (2004) Low bone mineral density is related to echogenic carotid artery plaques: a population-based study. Am J Epidemiol 160:549–556

    Article  PubMed  Google Scholar 

  7. Kawano KI, Ogata N, Chiano M, Molloy H, Kleyn P, Spector TD, Uchida M, Hosoi T, Suzuki T, Orimo H, Inoue S, Nabeshima Y, Nakamura K, Kuro O, Kawaguchi H (2002) Klotho gene polymorphisms associated with bone density of aged postmenopausal women. J Bone Miner Res 17:1744–1751

    Article  PubMed  CAS  Google Scholar 

  8. Ogata N, Matsumura Y, Shiraki M, Kawano K, Koshizuka Y, Hosoi T, Nakamura K, Kuro-o M, Kawaguchi H (2002) Association of klotho gene polymorphism with bone density and spondylosis of the lumbar spine in postmenopausal women. Bone 31:37–42

    Article  PubMed  CAS  Google Scholar 

  9. Yamada Y, Ando F, Niino N, Shimokata H (2005) Association of polymorphisms of the androgen receptor and klotho genes with bone mineral density in Japanese women. J Mol Med 83:50–57

    Article  PubMed  CAS  Google Scholar 

  10. Valero C, Zarrabeitia MT, Hernandez JL, Zarrabeitia MT, González-Macías J, Riancho JA (2005) Bone mass in young adults: relationship with gender, weight, and genetic factors. J Intern Med 258:554–562

    Article  PubMed  CAS  Google Scholar 

  11. Gauderman WJ (2002) Sample size requirements for association studies of gene-gene interaction. Am J Epidemiol 155:478–484

    Article  PubMed  Google Scholar 

  12. Mullin BH, Wilson SG, Islam FM, Calautti M, Dick IM, Devine A, Prince RL (2005) Klotho gene polymorphisms are associated with osteocalcin levels but not bone density of aged postmenopausal women. Calcif Tissue Int 77:145–151

    Article  PubMed  CAS  Google Scholar 

  13. Riancho JA, Valero C, Hernandez JL, Ortiz F, Zarrabeitia A, Alonso MA, Peña N, Pascual MA, Gonzalez Macias J, Zarrabeitia MT (2006) Association of the F352V variant of the klotho gene with bone mineral density. Biogerontology [epub ahead of print, DOI: 10.1007/s10522-066-9039-5]

  14. Koller DL, Ichikawa S, Johnson ML, Lai D, Xuei X, Edenberg KJ, Conneally PM, Hui SL, Johnston CC, Peacock M, Foroud T, Econs MJ (2005) Contribution of the LRP5 gene to normal variation in peak BMD in women. J Bone Miner Res 20:75–80

    Article  PubMed  CAS  Google Scholar 

  15. Riancho JA, Zarrabeitia MT, Valero C, Sañudo C, Hernandez JL, Amado JA, Zarrabeitia A, Gonzalez-Macias J (2005) Aromatase gene and osteoporosis: relationship of ten polymorphic loci with bone mineral density. Bone 36:917–925

    Article  PubMed  CAS  Google Scholar 

  16. Zarrabeitia A, Zarrabeitia MT, Valero C, González-Macías J, Riancho JA (2004) Age-related influence of common aromatase gene polymorphisms on bone mass of healthy men. Bone 35:243–248

    Article  PubMed  CAS  Google Scholar 

  17. Zarrabeitia MT, Hernandez JL, Valero C, Zarrabeitia AL, Garcia-Unzueta MT, Amado JA, Gonzalez-Macias J, Riancho JA (2004) A common polymorphism in the 5’-untranslated region of the aromatase gene influences bone mass and fracture risk. Eur J Endocrinol 150:699–704

    Article  PubMed  CAS  Google Scholar 

  18. Kawaguchi H, Manabe N, Miyaura C, Chikuda H, Nakamura K, Kuro-o M (1999) Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia. J Clin Invest 104:229–237

    Article  PubMed  CAS  Google Scholar 

  19. Kawaguchi H, Manabe N, Chikuda H, Nakamura K, Kuroo M (2000) Cellular and molecular mechanism of low-turnover osteopenia in the klotho-deficient mouse. Cell Mol Life Sci 57:731–737

    Article  PubMed  CAS  Google Scholar 

  20. Yamashita T, Nabeshima Y, Noda M (2000) High-resolution micro-computed tomography analyses of the abnormal trabecular bone structures in klotho gene mutant mice. J Endocrinol 164:239–245

    Article  PubMed  CAS  Google Scholar 

  21. Yamashita T, Yoshitake H, Tsuji K, Kawaguchi N, Nabeshima Y, Noda M (2000) Retardation in bone resorption after bone marrow ablation in klotho mutant mice. Endocrinology 141:438–445

    Article  PubMed  CAS  Google Scholar 

  22. Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nobeshima Y (1998) Identification of the human Klotho gene and its two transcripts encoding membrane and secreted Klotho protein. Biochem Biophys Res Commun 242:626–630

    Article  PubMed  CAS  Google Scholar 

  23. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M (2005) Suppression of aging in mice by the hormone klotho. Science 309:1829–1833

    Article  PubMed  CAS  Google Scholar 

  24. Ikushima M, Rakugi H, Ishikawa K, Maekawa Y, Yamamoto K, Ohta J, Chihara Y, Kida I, Ogihara T (2005) Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells. Biochem Biophys Res Commun 339:827–832

    Article  PubMed  CAS  Google Scholar 

  25. Chang Q, Hoefs S, van der Kemp AW, Topala CN, Bindels RJ, Hoenderop JG (2005) The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science 310:490–493

    Article  PubMed  CAS  Google Scholar 

  26. Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M (2006) Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 281:6120–6123

    Article  PubMed  CAS  Google Scholar 

  27. Tohyama O, Imura A, Iwano A, Freund JN, Henrissat B, Fujimori T, Nabeshima Y (2004) Klotho is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides. J Biol Chem 279:9777–9784

    Article  PubMed  CAS  Google Scholar 

  28. Chihara Y, Rakugi H, Ishikawa K, Ikushima M, Maekawa Y, Ohta J, Kida I, Ogihara T (2006) Klotho protein promotes adipocyte differentiation. Endocrinology 147:3835–3842

    Article  PubMed  CAS  Google Scholar 

  29. Gimble JM, Zvonic S, Floyd ZE, Kassem M, Nuttall ME (2006) Playing with bone and fat. J Cell Biochem 98:251–266

    Article  PubMed  CAS  Google Scholar 

  30. Hamrick MW (2004) Leptin, bone mass, and the thrifty phenotype. J Bone Miner Res 19:1607–1611

    Article  PubMed  CAS  Google Scholar 

  31. Hamrick MW, Della-Fera MA, Choi YH, Pennington C, Hartzell D, Baile CA (2005) Leptin treatment induces loss of bone marrow adipocytes and increases bone formation in leptin-deficient ob/ob mice. J Bone Miner Res 20:994–1001

    Article  PubMed  CAS  Google Scholar 

  32. Abdallah BM, Haack-Sorensen M, Fink T, Kassem M (2006) Inhibition of osteoblast differentiation but not adipocyte differentiation of mesenchymal stem cells by sera obtained from aged females. Bone 39:181–188

    Article  PubMed  Google Scholar 

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Acknowledgement

We thank Blanca Paule and Carolina Sañudo for excellent technical assistance. This work was supported by a grant from Fundación Marqués de Valdecilla-IFIMAV.

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Authors and Affiliations

  1. Unit of Legal Medicine, University of Cantabria, Av. Herrera Oria sn, 39008, Santander, Spain

    M. T. Zarrabeitia

  2. Department of Internal Medicine, Hospital U. M. Valdecilla, University of Cantabria, Av. Valdecilla sn, 39008, Santander, Spain

    J. L. Hernández, C. Valero, A. L. Zarrabeitia, F. Ortiz, J. Gonzalez-Macias & J. A. Riancho

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  1. M. T. Zarrabeitia
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  2. J. L. Hernández
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  3. C. Valero
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  4. A. L. Zarrabeitia
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  5. F. Ortiz
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  6. J. Gonzalez-Macias
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  7. J. A. Riancho
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Correspondence to J. A. Riancho.

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Zarrabeitia, M.T., Hernández, J.L., Valero, C. et al. Klotho Gene Polymorphism and Male Bone Mass. Calcif Tissue Int 80, 10–14 (2007). https://doi.org/10.1007/s00223-006-0233-x

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  • DOI: https://doi.org/10.1007/s00223-006-0233-x

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