Abstract
Background
Osteoprotegerin (OPG) is a recently identified cytokine, which acts as a decoy receptor for the receptor activator of the NF-κB ligand (RANKL), and has also been shown to be an important inhibitor of osteoclastogenesis in animal models. However, the relationship between OPG gene polymorphism and female bone stati in human populations is unclear. In this study, the relationship between OPG gene polymorphisms and bone mineral metabolism in healthy Korean women was investigated.
Methods
We observed 251 healthy women (mean age, 51.3 ± 6.9 yr). The serum OPG concentrations were determined using ELISA, and the biochemical markers of bone turnover and FSH measured using standard methods. The bone mineral densities at the lumbar spine and femoral neck were measured by dual energy x-ray absorptiometry. The A163G, G209A, T245G and T950C polymorphisms of the OPG gene were analyzed by allelic discrimination using the 5 nuclease polymerase chain reaction assay.
Results
The lumbar spine BMD of premenopausal women was marginally decreased in the variant allele group compared to the wild type group (A163G, 0.98 ± 0.14 g/cm2 [GG + GA] vs. 1.05 ± 0.15 g/cm2 [AA], P = 0.070; T245G, 0.97 ± 0.13 g/cm2 [GG + GT] vs. 1.04 ± 0.15 g/cm2 [TT], P = 0.056). In the linkage of polymorphisms A163G and T245G, the lumbar spine BMD of premenopausal women was marginally decreased in the variant allele group compared to the wild type group ([AATT] vs. [AGTG + AGGG + GGTG + GGGG]: 1.04 ± 0.15 vs. 0.97 ± 0.13; P = 0.072). However, there were no differences in the serum OPG levels and bone turnover markers among the different genotypes.
Figures and Tables
References
1. Looker AC, Orwoll ES, Johnston CC Jr, Lindsay RL, Wahner HW, Dunn WL, Calvo MS, Harris TB, Heyse SP. Prevalence of low femoral bone density in older U.S. adults from NHANES III. J Bone Miner Res. 1997. 12:1761–1768.
2. Melton LJ 3rd, Chrischilles EA, Cooper C, Lane AW, Riggs BL. Perspective. How many women have osteoporosis? J Bone Miner Res. 1992. 7:1005–1010.
3. Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA. Prediction of bone density from vitamin D receptor alleles. Nature. 1994. 367:284–287.
4. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med. 1994. 331:1056–1061.
5. Grant SF, Reid DM, Blake G, Herd R, Fogelman I, Ralston SH. Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene. Nat Genet. 1996. 14:203–205.
6. Lim SK, Park YS, Park JM, Song YD, Lee EJ, Kim KR, Lee HC, Huh KB. Lack of association between vitamin D receptor genotypes and osteoporosis in Koreans. J Clin Endocrinol Metab. 1995. 80:3677–3681.
7. Han K, Choi J, Moon I, Yoon H, Han I, Min H, Kim Y, Choi Y. Non-association of estrogen receptor genotypes with bone mineral density and bone turnover in Korean pre-, peri-, and postmenopausal women. Osteoporos Int. 1999. 9:290–295.
8. Han KO, Moon IG, Hwang CS, Choi JT, Yoon HK, Min HK, Han IK. Lack of an intronic Sp1 binding-site polymorphism at the collagen type I alpha1 gene in healthy Korean women. Bone. 1999. 24:135–137.
9. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Boyle WJ, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997. 89:309–319.
10. Tsuda E, Goto M, Mochizuki S, Yano K, Kobayashi F, Morinaga T, Higashio K. Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun. 1997. 234:137–142.
11. Kwon BS, Wang S, Udagawa N, Haridas V, Lee ZH, Kim KK, Oh KO, Greene J, Li Y, Su J, Gentz R, Aggarwal BB, Ni J. TR1, a new member of the tumor necrosis factor receptor superfamily, induces fibroblast proliferation and inhibits osteoclastogenesis and bone resorption. FASEB J. 1998. 12:845–854.
12. Schoppet M, Preissner KT, Hofbauer LC. RANK ligand and osteoprotegerin: paracrine regulators of bone metabolism and vascular function. Arterioscler Thromb Vasc Biol. 2002. 22:549–553.
13. Khosla S. Minireview: The OPG/RANKL/RANK system. Endocrinology. 2001. 142:5050–5055.
14. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999. 397:315–323.
15. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998. 12:1260–1268.
16. Mizuno A, Amizuka N, Irie K, Murakami A, Fujise N, Kanno T, Sato Y, Nakagawa N, Yasuda H, Mochizuki S, Gomibuchi T, Yano K, Shima N, Washida N, Tsuda E, Morinaga T, Higashio K, Ozawa H. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun. 1998. 247:610–615.
17. Yasuda H, Shima N, Nakagawa N, Mochizuki SI, Yano K, Fujise N, Sato Y, Goto M, Yamaguchi K, Kuriyama M, Kanno T, Murakami A, Tsuda E, Morinaga T, Higashio K. Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/ OCIF inhibits osteoclastogenesis in vitro. Endocrinology. 1998. 139:1329–1337.
18. Min H, Morony S, Sarosi I, Dunstan CR, Capparelli C, Scully S, Van G, Kaufman S, Kostenuik PJ, Lacey DL, Boyle WJ, Simonet WS. Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med. 2000. 192:463–474.
19. Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, Dul E, Appelbaum ER, Eichman C, DiPrinzio R, Dodds RA, James IE, Rosenberg M, Lee JC, Young PR. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem. 1998. 273:14363–14367.
20. Miyamoto A, Kunisada T, Hemmi H, Yamane T, Yasuda H, Miyake K, Yamazaki H, Hayashi SI. Establishment and characterization of an immortal macrophage-like cell line inducible to differentiate to osteoclasts. Biochem Biophys Res Commun. 1998. 242:703–709.
21. Akatsu T, Murakami T, Nishikawa M, Ono K, Shinomiya N, Tsuda E, Mochizuki S, Yamaguchi K, Kinosaki M, Higashio K, Yamamoto M, Motoyoshi K, Nagata N. Osteoclastogenesis inhibitory factor suppresses osteoclast survival by interfering in the interaction of stromal cells with osteoclast. Biochem Biophys Res Commun. 1998. 250:229–234.
22. Hakeda Y, Kobayashi Y, Yamaguchi K, Yasuda H, Tsuda E, Higashio K, Miyata T, Kumegawa M. Osteoclastogenesis inhibitory factor (OCIF) directly inhibits bone-resorbing activity of isolated mature osteoclasts. Biochem Biophys Res Commun. 1998. 251:796–801.
23. Burgess TL, Qian Y, Kaufman S, Ring BD, Van G, Capparelli C, Kelley M, Hsu H, Boyle WJ, Dunstan CR, Hu S, Lacey DL. The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. J Cell Biol. 1999. 145:527–538.
24. Jimi E, Akiyama S, Tsurukai T, Okahashi N, Kobayashi K, Udagawa N, Nishihara T, Takahashi N, Suda T. Osteoclast differentiation factor acts as a multifunctional regulator in murine osteoclast differentiation and function. J Immunol. 1999. 163:434–442.
25. Hofbauer LC, Gori F, Riggs BL, Lacey DL, Dunstan CR, Spelsberg TC, Khosla S. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology. 1999. 140:4382–4389.
26. Khosla S, Arrighi HM, Melton LJ 3rd, Atkinson EJ, O'Fallon WM, Dunstan C, Riggs BL. Correlates of osteoprotegerin levels in women and men. Osteoporos Int. 2002. 13:394–399.
27. Szulc P, Hofbauer LC, Heufelder AE, Roth S, Delmas PD. Osteoprotegerin serum levels in men: correlation with age, estrogen, and testosterone status. J Clin Endocrinol Metab. 2001. 86:3162–3165.
28. Rogers A, Saleh G, Hannon RA, Greenfield D, Eastell R. Circulating estradiol and osteoprotegerin as determinants of bone turnover and bone density in postmenopausal women. J Clin Endocrinol Metab. 2002. 87:4470–4475.
29. Oh KW, Rhee EJ, Lee WY, Kim SW, Oh ES, Baek KH, Kang MI, Choi MG, Yoo HJ, Park SW. The relationship between circulating osteoprotegerin levels and bone mineral metabolism in healthy women. Clin Endocrinol (Oxf). 2004. 61:244–249.
30. Oh KW, Rhee EJ, Lee WY, Kim SW, Baek KH, Kang MI, Yun EJ, Park CY, Ihm SH, Choi MG, Yoo HJ, Park SW. Circulating osteoprotegerin and receptor activator of NF-κB ligand system are associated with bone metabolism in middle-aged males. Clin Endocrinol (Oxf). 2005. 62:92–98.
31. Langdahl BL, Carstens M, Stenkjaer L, Eriksen EF. Polymorphisms in the osteoprotegerin gene are associated with osteoporotic fractures. J Bone Miner Res. 2002. 17:1245–1255.
32. Jorgensen HL, Kusk P, Madsen B, Fenger M, Lauritzen JB. Serum osteoprotegerin (OPG) and the A163G polymorphism in the OPG promoter region are related to peripheral measures of bone mass and fracture odds ratios. J Bone Miner Metab. 2004. 22:132–138.
33. Arko B, Prezelj J, Komel R, Kocijancic A, Hudler P, Marc J. Sequence variations in the osteoprotegerin gene promoter in patients with postmenopausal osteoporosis. J Clin Endocrinol Metab. 2002. 87:4080–4084.
34. Yamada Y, Ando F, Niino N, Shimokata H. Association of polymorphisms of the osteoprotegerin gene with bone mineral density in Japanese women but not men. Mol Genet Metab. 2003. 80:344–349.
35. Soufi M, Schoppet M, Sattler AM, Herzum M, Maisch B, Hofbauer LC, Schaefer JR. Osteoprotegerin gene polymorphisms in men with coronary artery disease. J Clin Endocrinol Metab. 2004. 89:3764–3768.
36. Wynne F, Drummond F, O'Sullivan K, Daly M, Shanahan F, Molloy MG, Quane KA. Investigation of the genetic influence of the OPG, VDR (Fok1), and COLIA1 Sp1 polymorphisms on BMD in the Irish population. Calcif Tissue Int. 2002. 71:26–35.
37. Brandstrom H, Gerdhem P, Stiger F, Obrant KJ, Melhus H, Ljunggren O, Kindmark A, Akesson K. Single nucleotide polymorphisms in the human gene for osteoprotegerin are not related to bone mineral density or fracture in elderly women. Calcif Tissue Int. 2004. 74:18–24.