Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Bone Metabolism and Estrogenic Effect of Phytochemicals

골 대사 및 phytochemicals의 estrogen 효과

  • Kim, Bokyung (Department of Food and Nutrition, Silla University) ;
  • Kim, Mihyang (Department of Food and Nutrition, Silla University)
  • 김보경 (신라대학교 식품영양학과) ;
  • 김미향 (신라대학교 식품영양학과)
  • Received : 2018.07.13
  • Accepted : 2018.07.25
  • Published : 2018.07.30
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Abstract

Osteoporosis is a disease that increases the risk of fracture by decreasing the mass and strength of bone. It is caused by imbalance of osteoclast bone formation and osteoclast bone resorption. Bone formation by osteoblast is activated via bone morphogenetic proteins and runt-related transcription factor 2. $Wnt/{\beta}-catenin$ signaling and bone resorption by osteoclast are initiated by the binding of receptor activator of nuclear $factor-{\kappa}B$ ligand and receptor activator of nuclear $factor-{\kappa}B$. Menopausal women are at risk for many diseases due to hormonal imbalances, and osteoporosis is the most common metabolic disorder in 30% of postmenopausal women. When estrogen is deficient, bone resorption of osteoclasts is promoted, and the risk of osteoporosis especially increases in postmenopausal women. Hormone replacement therapy has been widely used to relieve or treat the symptoms of menopausal syndrome. However, long-term administration of hormone therapy has been associated with a high risk of side effects, such as breast cancer, ovarian cancer, and uterine cancer. Recently, phytochemicals have been actively studied as a phytoestrogen, which has an estrogen-like activity to cope with symptoms of menopausal syndrome. Therefore, in this review, we investigated the differentiation mechanism of osteoblast and osteoclast and the role of estrogen and phytoestrogen in bone metabolism in relation to previous studies.

전 세계적인 인구 고령화 현상으로 인하여 골다공증은 주요한 질병으로 대두되고 있다. 골다공증은 뼈의 질량과 강도가 감소하여 골절의 위험이 증가하는 질환으로 조골세포의 골 형성 및 파골세포의 골 흡수의 불균형으로 인해 발생하는 질환이다. 조골세포에 의한 골 형성은 BMP, RUNX2, $Wnt/{\beta}-catenin$ 경로 등을 통하여 활성화 되며, 파골세포에 의한 골 흡수는 RANKL과 RANK의 결합에 의해서 시작된다. 폐경기 여성은 호르몬 불균형에 의해 여러 질병의 위험에 처해 있으며, 폐경기 여성의 약 30%에서 관찰되는 골다공증은 폐경기 여성에게서 발생되는 가장 흔한 대사성 질환이기도 하다. Estrogen이 부족할 때 파골세포의 골 흡수가 촉진되므로, 특히 폐경 여성에서 골다공증의 발생위험이 증가하게 된다. 호르몬대체요법은 폐경기 증후군의 증상을 경감시키거나 치료하기 위해 널리 사용되어 왔으나, 호르몬 치료를 장기간 실시할 경우 유방암, 난소암, 자궁암 등의 부작용 위험성이 매우 높은 것으로 알려져 있다. 따라서 최근 들어 여러 부작용을 보완하기 위해 폐경기 증후군 증상에 대처할 수 있는 estrogen과 유사한 활성을 지닌 식물성 estrogen인 phytoestrogen에 대한 연구가 활발히 진행되고 있다. 따라서, 본 총설에서는 조골세포 및 파골세포의 분화 기전에 대한 선행연구를 알아보고 골 대사에서의 estrogen의 역할 및 phytoestrogen과 관련한 연구들에 대해서도 살펴보았다.

Keywords

References

  1. Akune, T., Ohba, S., Kamekura, S., Yamaguchi, M., Chung, U. I, Kubota, N., Terauchi, Y., Harada, Y., Azuma, Y., Nakamura, K., Kadowaki, T. and Kawaguchi, T. 2004. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J. Clin. Invest. 113, 846-855. https://doi.org/10.1172/JCI200419900
  2. Asagiri, M., Sato, K., Usami, T., Ochi, S., Nishina, H., Yoshida, H., Morita, I., Wagner, E. F., Mak, T. W. and Serfling, E. 2005. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J. Exp. Med. 202, 1261-1269. https://doi.org/10.1084/jem.20051150
  3. Asagiri, M. and Takayanagi, H. 2007. The molecular understanding of osteoclast differentiation. Bone 40, 251-264. https://doi.org/10.1016/j.bone.2006.09.023
  4. Aubin, J. E., Liu, F., Malaval, L. and Gupta, A. K. 1995. Osteoblast and chondroblast differentiation. Bone 17, S77-S83. https://doi.org/10.1016/8756-3282(95)00183-E
  5. Bae, S. J. 2012. Estrogen deficiency stimulates sclerostin expression by TNF-${\alpha}$. PhD Thesis, Ulsan University.
  6. Belchetz, P. E. 1994. Hormonal treatment of postmenopausal women. N. Engl. J. Med. 330, 1062-1071. https://doi.org/10.1056/NEJM199404143301508
  7. Boyle, W. J., Simonet, W. S. and Lacey, D. L. 2003. Osteoclast differentiation and activation. Nature 423, 337. https://doi.org/10.1038/nature01658
  8. Bucay, N., Sarosi, I., Dunstan, C. R., Morony, S., Tarpley, J., Capparelli, C., Scully, S.,. Tan, H. L., Xu, W., Lacey, D. L., Boyle, W. J. and Simonet, W. S. 1998. OsteoprotegerinDeficient Mice Develop Early Onset Osteoporosis and Arterial Calcification. Genes Dev. 12, 1260-1268. https://doi.org/10.1101/gad.12.9.1260
  9. Byun, J. S., Rho, S. N., Park, J. S. and H. Park, H. M. 2005. Effect of isoflavone supplementation on bone metabolism in ovariectomized rats at different ages. Kor. J. Food Nutr. 34, 1350-1356. https://doi.org/10.3746/jkfn.2005.34.9.1350
  10. Cauley, J. A. 2015. Estrogen and bone health in men and women. Steroids 99, 11-15. https://doi.org/10.1016/j.steroids.2014.12.010
  11. Chakladar, A., Dubeykovskiy, A., Wojtukiewicz, L. J., Pratap, J., Lei, S. and Wang, T. C. 2005. Synergistic activation of the murine gastrin promoter by oncogenic Ras and ${\beta}$-catenin involves SMAD recruitment. Biochem. Biophys. Res. Commun. 336, 190-196. https://doi.org/10.1016/j.bbrc.2005.08.061
  12. Cheon, J. S. 2003. Reproductive psychiatry: perimenopause and menopause. J. Kor. Neuropsychiatr Assoc. 42, 46-53.
  13. Choi, J. Y., Lee, B. H., Song, K. B., Park, R. W., Kim, I. S., Sohn, K. Y., Jo, J. S. and Ryoo, H. M. 1996. Expression patterns of bone-related proteins during osteoblastic differentiation in MC3T3-E1 cells. J. Cell. Biochem. 61, 609-618. https://doi.org/10.1002/(SICI)1097-4644(19960616)61:4<609::AID-JCB15>3.0.CO;2-A
  14. Chung, H. J., Kim, W. K., Park, H. J., Cho, L., Kim, M. R., Kim, M. J., Shin, J. H. Lee, J. H., Ha, I. H. and Lee, S. K. 2016. Anti-osteoporotic activity of harpagide by regulation of bone formation in osteoblast cell culture and ovariectomy-induced bone loss mouse models. J. Ethnopharmacol. 179, 66-75. https://doi.org/10.1016/j.jep.2015.12.025
  15. Edlund, S., Lee, S. Y., Grimsby, S., Zhang, S., Aspenstrom, P., Heldin, C. H. and Landstrom, M. 2005. Interaction between Smad7 and beta-catenin: importance for transforming growth factor beta-induced apoptosis. Nat. Rev. Mol. Cell Biol. 25, 1475-1488.
  16. Eisman, J. A. 1999. Genetics of osteoporosis. Endocr. Rev. 20, 788-804. https://doi.org/10.1210/edrv.20.6.0384
  17. Eivers, E., Demagny, H. and De Robertis, E. M. 2009. Integration of BMP and Wnt signaling via vertebrate Smad1/ 5/8 and Drosophila Mad. Cytokine Growth Factor Rev. 20, 357-365. https://doi.org/10.1016/j.cytogfr.2009.10.017
  18. Eivers, E., Demagny, H., Choi, R. H. and De Robertis, E. M. 2011. Phosphorylation of Mad controls competition between wingless and BMP signaling. Sci. Signal. 4, ra68.
  19. Elfituri, A., Sherif, F., Elmahaishi, M. and Chrystyn, H. 2005. Two hormone replacement therapy (HRT) regimens for middle-eastern postmenopausal women. Maturitas 52, 52-59. https://doi.org/10.1016/j.maturitas.2004.12.003
  20. Franceschi, R. T., Ge, C., Xiao, G., Roca, H. and Jiang, D. 2007. Transcriptional regulation of osteoblasts. Ann. N. Y. Acad. Sci. 1116, 196-207.
  21. Fuentealba, L. C., Eivers, E., Ikeda, A., Hurtado, V., Kuroda, H., Pera, E. M. and De Robertis, E. M. 2007. Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell 131, 980-993. https://doi.org/10.1016/j.cell.2007.09.027
  22. Fuji, H., Ohmae, S., Noma, N., Takeiri, M., Yasutomi, H., Izumi, K., Ito, M., Toyomoto, K., Iwaki, S., Takemoto, K., Seo, S., Taura, K., Hida, S., Aoyama, M., Ishihama, Y., Hagiwara, M., Takeda, N., Hatano, E., Iwaisako, K., Uemoto, S. and Asagiri, M. 2018. Necrostatin-7 suppresses RANKNFATc1 signaling and attenuates macrophage to osteoclast differentiation. Biochem. Biophys. Res. Commun. doi: 10.1016/ j.bbrc.2018.05.153.
  23. Golub, E. E. and Boesze-Battaglia, K. 2007. The role of alkaline phosphatase in mineralization. Curr. Orthop. Pract. 18, 444-448.
  24. Gu, Q., Chen, C., Zhang, Z., Wu, Z., Fan, X., Zhang, Z., Di, W. and Shi, L. 2015. Ginkgo biloba extract promotes osteogenic differentiation of human bone marrow mesenchymal stem cells in a pathway involving Wnt/${\beta}$-catenin signaling. Pharmacol. Res. 97, 70-78. https://doi.org/10.1016/j.phrs.2015.04.004
  25. Han, S. H., Kim, M. D., You, S. H., You, Y. O., You, H. K. and Shin, H. S. 2001. Effects of olibanum extracts on the activity and differentiation of MC3T3-E1 cells. J. Kor. Acad. Periodontol. 31, 287-298. https://doi.org/10.5051/jkape.2001.31.2.287
  26. Hu, M. C. and Rosenblum, N. D. 2005. Smad1, beta-catenin and Tcf4 associate in a molecular complex with the Myc promoter in dysplastic renal tissue and cooperate to control Myc transcription. Development 132, 215-225.
  27. Huh, J. S., Kang, J. H., Yoo, Y. J., Kim, C. S., Cho, K. S. and Choi, S. H. 2001. The effect of safflower seed fraction extract on periodontal ligament fibroblast and MC3T3-E1 cell in vitro. J. Kor. Acad. Periodontol. 31, 833-846. https://doi.org/10.5051/jkape.2001.31.4.833
  28. Hussein, S. M., Duff, E. K. and Sirard, C. 2003. Smad4 and beta-catenin co-activators functionally interact with lymphoid-enhancing factor to regulate graded expression of Msx2. J. Biol. Chem. 278, 48805-48814. https://doi.org/10.1074/jbc.M305472200
  29. Hwang, J. H., Lee, M. R., Kang, C. H. and Bu, H. J. 2016. Effects of sulraphane on osteoclastogenesis in RAW 264.7. J. Agric. Life Sci. 50, 151-160.
  30. Im, N. K., Kim, H. J., Kim, M. J., Lee, E. J., Kim, H. I. and Lee, I. S. 2010. Effects of medicinal herb extracts on osteoblast differentiation and osteoclast formation. Kor. J. Food Nutr. 42, 637-642.
  31. Jeon, S. K. 2008. Effects of Rosmarinus officinalis L. on the Activity and Differentiation Osteoblast cell. MS Thesis, Keimyung University.
  32. Ji, S. H, Ahn, D. H. and Jun, M. R. 2010. Effects of petasites japonicus and Momordica charantia L. extracts on MC3T3-E1 osteoblastic cells. Kor. J. Food Nutr. 39, 203-209. https://doi.org/10.3746/jkfn.2010.39.2.203
  33. Jun, Y. J., Lee, T. Y., Kong, M. H., Joo, N. S. and Park, S. B. 2007. Effect of osteoporosis therapy & bone marker change in peri menopousal women. J. Osteoporos. 5, 27-36.
  34. Jung, C. 2012. Aging society and labor market. J. Digit. Converg. 10, 185-194.
  35. Karst, M., Gorny, G., Galvin, R. J. S and Oursler, M. J. 2004. Roles of stromal cell RANKL, OPG, and M-CSF expression in biphasic TGF-${\beta}$ regulation of osteoclast differentiation. J. Cell. Physiol. 200, 99-106. https://doi.org/10.1002/jcp.20036
  36. Khalid, A. B. and. Krum, S. A. 2016. Estrogen receptors alpha and beta in bone. Bone 87, 130-135. https://doi.org/10.1016/j.bone.2016.03.016
  37. Kim, D. Y. 2014. The effects of collagen and collagen-containig foods on bone metabolism. MS Thesis, Sookmyung Women's University.
  38. Kim, K. M., Kim, T. H. and Jang, W. G. 2017. Effect of cryptochlorogenic acid extracted from fruits of sorbus commixta on osteoblast differentiation. Kor. J. Food Nutr. 46, 314-319. https://doi.org/10.3746/jkfn.2017.46.3.314
  39. Kim, K. M., Kim, T. H. and Jang, W. G. 2017. Effect of cryptochlorogenic acid extracted from fruits of sorbus commixta on osteoblast differentiation. Kor. J. Food Nutr. 46, 314-319. https://doi.org/10.3746/jkfn.2017.46.3.314
  40. Kim, M. B., Song, Y and Hwang, J. 2014. Kirenol stimulates osteoblast differentiation through activation of the BMP and Wnt/${\beta}$-catenin signaling pathways in MC3T3-E1 cells. Fitoterapia 98, 59-65. https://doi.org/10.1016/j.fitote.2014.07.013
  41. Kim, M. J., Im, N. K., Yu, M. H., Kim, H. J and Lee, L. S. 2011. Effects of extracts from sarcocarp, peels, and seeds of avocado on osteoblast differentiation and osteoclast formation. Kor. J. Food Nutr. 40, 919-927. https://doi.org/10.3746/jkfn.2011.40.7.919
  42. Komori, T. 2005. Regulation of skeletal development by the Runx family of transcription factors. J. Cell. Biochem. 95, 445-453. https://doi.org/10.1002/jcb.20420
  43. Labbe, E., Letamendia, A. and Attisano, L. 2000. Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-beta and wnt pathways. Proc. Natl. Acad. Sci. USA. 97, 8358-8363. https://doi.org/10.1073/pnas.150152697
  44. Lacey, D. L., Tan, H. L., Lu, J., Kaufman, S., Van, G., Qiu, W., Rattan, A., Scully, S., Fletcher, F. and Juan, T. 2000. Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo. Am. J. Pathol. 157, 435-448. https://doi.org/10.1016/S0002-9440(10)64556-7
  45. Lee, J. and Lee, I. 2004. Effects of Rubus coreanus Miquel extracts on the activity and differentiation of MC3T3-E1 osteoblastic cell. J. Life Sci. 14, 967-974. https://doi.org/10.5352/JLS.2004.14.6.967
  46. Lee, J. W., Kim, H. J., Jhee, O. H., Won, H. D., Yu, J. Y., Lee, M. H., Kim, T. W., Om, A. S. and Kang, J. S. 2005. Effects of alternative medicine extract on bone mineral density, bone strength and biochemical markers of bone metabolism in ovariectomized rats. Kor. J. Food Nutr. 18, 72-80.
  47. Lee, M. J., Lee, S. Y., Park, S. H and Ahn, D. W. 2010. Differential expression of RANKL and OPG by the PPAR gamma agonist rosiglitazone in osteoblasts. J. Kor. Soc. Osteoporos. 8, 47-55.
  48. Lee, S. H., Jung, B. H., Kim, S. Y and Chung, B. C. 2004. Determination of phytoestrogens in traditional medicinal herbs using gas chromatography-mass spectrometry. J. Nutr. Biochem. 15, 452-460. https://doi.org/10.1016/j.jnutbio.2004.01.007
  49. Lee, W. J and Kim, N. A. 2005. A statistical compare analysis of bone mineral density of lumbar spine and femur, risk factors for osteoporosis in the women of pre, postmenopausal. J. Radiol. Sci. Technol. 28, 227-234.
  50. Lee, Y. B., Lee, H. J., Kim, K. S., Lee, J. Y., Nam, S. Y., Cheon, S. H and Sohn, H. S. 2004. Evaluation of the preventive effect of isoflavone extract on bone loss in ovariectomized rats. Biosci. Biotechnol. Biochem. 68, 1040-1045. https://doi.org/10.1271/bbb.68.1040
  51. Lei, S., Dubeykovskiy, A., Chakladar, A., Wojtukiewicz, L and Wang, T. C. 2004. The murine gastrin promoter is synergistically activated by transforming growth factor-beta/Smad and Wnt signaling pathways. J. Biol. Chem. 279, 42492-42502. https://doi.org/10.1074/jbc.M404025200
  52. Li, F., Yang, Y., Zhu, P., Chen, W., Qi, D., Shi, X., Zhang, C., Yang, Z. and Li, P. 2012. Echinacoside promotes bone regeneration by increasing OPG/RANKL ratio in MC3T3-E1 cells. Fitoterapia 83, 1443-1450. https://doi.org/10.1016/j.fitote.2012.08.008
  53. Li, J., Hao, L., Wu, J., Zhang, J. and Su, J. 2016. Linarin promotes osteogenic differentiation by activating the BMP-2/ RUNX2 pathway via protein kinase A signaling. Int. J. Mol. Med. 37, 901-910. https://doi.org/10.3892/ijmm.2016.2490
  54. Li, K., Zhang, X., He, B., Yang, R., Zhang, Y., Shen, Z., Chen, P. and Du, W. 2018. Geraniin promotes osteoblast proliferation and differentiation via the activation of Wnt/${\beta}$-catenin pathway. Biomed. Pharmacother. 99, 319-324. https://doi.org/10.1016/j.biopha.2018.01.040
  55. Liu, Z., Tang, Y., Qiu, T., Cao, X. and Clemens, T. L. 2006. A dishevelled-1/Smad1 interaction couples WNT and bone morphogenetic protein signaling pathways in uncommitted bone marrow stromal cells. J. Biol. Chem. 281, 17156-17163. https://doi.org/10.1074/jbc.M513812200
  56. Marie, P. J. 2008. Transcription factors controlling osteoblastogenesis. Arch. Biochem. Biophys. 473, 98-105. https://doi.org/10.1016/j.abb.2008.02.030
  57. Martin, P. M., Horwitz, K. B., Ryan, D. S and Mcguire, W. L. 1978. Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinology 103, 1860-1867. https://doi.org/10.1210/endo-103-5-1860
  58. Jeon, M. H. and Kim, M. H. 2011. Effect of Hijikia fusiforme fractions on proliferation and differentiation in osteoblastic MC3T3-E1 cells. J. Life Sci. 21, 300-308. https://doi.org/10.5352/JLS.2011.21.2.300
  59. Mok, S. K., You, H. K. and Shin, H. S. 1996. The effects of prostaglandin and dibutyryl cAMP on osteoblastic cell activity and osteoclast generation. J. Periodontal Implant Sci. 26, 448-468.
  60. Nurdiana, N., Mariati, N., Noorhamdani, N., Setiawan, B. Budhiparama, N. and Noor, Z. 2018. Effects of Labisia pumila on bone turnover markers and OPG/RANKL system in a rat model of post-menopausal osteoporosis. Clin. Nutr. Exp. 20, 41-47. https://doi.org/10.1016/j.yclnex.2018.01.002
  61. Park, J., Lee, J., Kim, H. and Lee, I. 2005. Effects of Solidago virga-aurea var. gigantea Miq. root extracts on the activity and differentiation of MC3T3-E1 osteoblastic cell. Kor. J. Food Nutr. 34, 929-936. https://doi.org/10.3746/jkfn.2005.34.7.929
  62. Pols, H. A., Felsenberg, D., Hanley, D. A., Stepan, J., Munoz-Torres, M., Wilkin, T. J., Qin-Sheng, G., Galich, A. M., Vandormael, K. and Yates, A. 1999. Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT study. Osteoporosis Int. 9, 461-468. https://doi.org/10.1007/PL00004171
  63. Porwal, K., Pal, S., Dev, K., China, S. P., Kumar, Y., Singh, C., Barbhuyan, T., Sinha, N., Sanyal, S., Trivedi, A. K., Maurya, R. and Chattopadhyay, N. 2017. Guava fruit extract and its triterpene constituents have osteoanabolic effect: Stimulation of osteoblast differentiation by activation of mi-tochondrial respiration via the Wnt/${\beta}$-catenin signaling. J. Nutr. Biochem. 44, 22-34. https://doi.org/10.1016/j.jnutbio.2017.02.011
  64. Roggia, C., Gao, Y., Cenci, S., Weitzmann, M. N., Toraldo, G., Isaia, G. and Pacifici, R. 2001. Up-regulation of TNF-producing T cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo. Proc. Natl. Acad. Sci. USA. 98, 13960-13965. https://doi.org/10.1073/pnas.251534698
  65. Roodman, G. D. 2006. Regulation of osteoclast differentiation. Ann. N. Y. Acad. Sci. 1068, 100-109. https://doi.org/10.1196/annals.1346.013
  66. Sakai, D., Tanaka, Y., Endo, Y., Osumi, N., Okamoto, H. and Wakamatsu, Y. 2005. Regulation of Slug transcription in embryonic ectoderm by ${\beta}$-catenin-Lef/Tcf and BMP-Smad signaling. Dev. Growth Differ. 47, 471-482. https://doi.org/10.1111/j.1440-169X.2005.00821.x
  67. Satue, M., del Mar Arriero, M., Monjo, M. and Ramis, J. M. 2013. Quercitrin and taxifolin stimulate osteoblast differentiation in MC3T3-E1 cells and inhibit osteoclastogenesis in RAW 264.7 cells. Biochem. Pharmacol. 86, 1476-1486. https://doi.org/10.1016/j.bcp.2013.09.009
  68. Son, B. S., Do, H. H., Kim, E. G., Youn, B. H. and Kim, W. Y. 2017. Circadian clock genes, PER1 and PER2, as tumor suppressors. J. Life Sci. 27, 1225-1231.
  69. Spilmont, M., Leotoing, L., Davicco, M. J., Lebecque, P., Mercier, S., Miot-Noirault, E., Pilet, P., Rios, L., Wittrant, Y. and Coxam, V. 2013. Pomegranate seed oil prevents bone loss in a mice model of osteoporosis, through osteoblastic stimulation, osteoclastic inhibition and decreased inflammatory status. J. Nutr. Biochem. 24, 1840-1848. https://doi.org/10.1016/j.jnutbio.2013.04.005
  70. Stein, G. S., Lian, J. B. and Owen, T. A. 1990. Relationship of cell growth to the regulation of tissue-specific gene expression during osteoblast differentiation. FASEB J. 4, 3111-3123. https://doi.org/10.1096/fasebj.4.13.2210157
  71. Sun, J., Sun, W. J., Li, Z. Y., Li, L., Wang, Y., Zhao, Y., Wang, C., Yu, L. R., Li, L. Z. and Zhang, Y. L. 2016. Daidzein increases OPG/RANKL ratio and suppresses IL-6 in MG-63 osteoblast cells. Int. Immunopharmacol. 40, 32-40. https://doi.org/10.1016/j.intimp.2016.08.014
  72. Tang, Y., Liu, Z., Zhao, L., Clemens, T. L. and Cao, X. 2008. Smad7 stabilizes beta-catenin binding to E-cadherin complex and promotes cell-cell adhesion. J. Biol. Chem. 283, 23956-23963. https://doi.org/10.1074/jbc.M800351200
  73. Tiyasatkulkovit, W., Charoenphandhu, N., Wongdee, K., Thongbunchoo, J., Krishnamra, N. and Malaivijitnond, S. 2012. Upregulation of osteoblastic differentiation marker mRNA expression in osteoblast-like UMR106 cells by puerarin and phytoestrogens from Pueraria mirifica. Phytomedicine 19, 1147-1155. https://doi.org/10.1016/j.phymed.2012.07.010
  74. Torii, Y., Hotomi, K., Yamagishi, Y. and Tsukagoshi, N. 1996. Demonstration of alkaline phosphatase participation in the mineralization of osteoblasts by antisense RNA approach. Cell Biol. Int. 20, 459-464. https://doi.org/10.1006/cbir.1996.0060
  75. Vaananen, H. K. and Horton, M. 1995. The osteoclast clear zone is a specialized cell-extracellular matrix adhesion structure. J. Cell. Sci. 108, 2729-2732.
  76. Walsh, M. C. and Choi, Y. 2014. Biology of the RANKL- RANK-OPG system in immunity, bone, and beyond. Front Immunol. 5, 511.
  77. Whittington, R. and Faulds, D. 1994. Hormone replacement therapy. Pharmacoeconomics 5, 419-445. https://doi.org/10.2165/00019053-199405050-00008
  78. Yin, X., Wang, X., Hu ,X., Chen, Y., Zeng, K. and Zhang, H. 2015. $ER{\beta}$ induces the differentiation of cultured osteoblasts by both Wnt/${\beta}$-catenin signaling pathway and estrogen signaling pathways. Exp. Cell Res. 335, 107-114. https://doi.org/10.1016/j.yexcr.2015.04.020
  79. Yoon, Y. N. 2007. The study of Bio-material Effects on the Osteoblast and Osteoclast Differentiation. MS Thesis, Sookmyung Women's University.
  80. Yu, F., Liu, Z. Tong, Z., Zhao, Z. and Liang, H. 2015. Soybean isoflavone treatment induces osteoblast differentiation and proliferation by regulating analysis of Wnt/${\beta}$-catenin pathway. Gene 573, 273-277. https://doi.org/10.1016/j.gene.2015.07.054
  81. Yun, H. M., Park, K. R., Quang, T. H., Oh, H., Hong, J. T., Kim, Y. C and Kim, E. C. 2015. 2, 4, 5-Trimethoxyldalbergiquinol promotes osteoblastic differentiation and mineralization via the BMP and Wnt/${\beta}$-catenin pathway. Cell Death Dis. 6, e1819. https://doi.org/10.1038/cddis.2015.185
  82. Yun, J. H., Hwang, E. S. and Kim, G. H. 2011. Effects of Chrysanthemum indicum L. extract on the growth and differentiation of osteoblastic MC3T3-E1 Cells. Kor. J. Food Nutr. 40, 1384-1390. https://doi.org/10.3746/jkfn.2011.40.10.1384
  83. Zhang, R., Oyajobi, B. O., Harris, S. E., Chen, D., Tsao, C., Deng, H. W. and Zhao, M. 2013. Wnt/${\beta}$-catenin signaling activates bone morphogenetic protein 2 expression in osteoblasts. Bone 52, 145-156. https://doi.org/10.1016/j.bone.2012.09.029
  84. Zhang, Z. R., Leung, W. N., Li, G., Kong, S. K., Lu, X., Wong, Y . M. and Chan, C. W. 2017. Osthole enhances osteogenesis in osteoblasts by elevating transcription factor osterix via cAMP/CREB signaling in vitro and in vivo. Nutrients 9, 588. https://doi.org/10.3390/nu9060588