选择性雌激素受体调节剂的作用机制及其治疗绝经后骨质疏松症的研究现状

中国临床药理学与治疗学 ›› 2008, Vol. 13 ›› Issue (2): 213-219.

选择性雌激素受体调节剂的作用机制及其治疗绝经后骨质疏松症的研究现状

李孟森¹, 周升², 李刚¹

¹北京大学医学部生物化学与分子生物学系, 北京 100083;
²海南医学院分析化学实验室, 海口 571101, 海南

收稿日期:2007-10-20 修回日期:2008-01-22 出版日期:2008-02-26 发布日期:2020-10-14
通讯作者: 李刚, 男, 教授, 博士生导师, 研究方向:真核细胞基因表达调控。Tel:010-82802891 E-mail:ligang55@bjmu.edu.cn
作者简介:李孟森, 男, 博士研究生, 副教授, 研究方向:肝癌细胞核受体表达调控。Tel:010-82802991 　E-mail:mengsenli@163.com
基金资助:
国家自然科学基金资助项目(30660071, 30760090)

Advances on mechanisms of selective estrogen receptor modulators and their therapy of postmenopausal osteoporosis

LI Meng-Sen¹, ZHOU Sheng², LI Gang¹

¹Department of Biochemistry and Molecular Biology, Health Science Center, Peking University,Beijing 100083, China;
²Laboratory of Analysis Chemistry, Hainan Medical College, Haikou 571101, Hainan,China

Received:2007-10-20 Revised:2008-01-22 Online:2008-02-26 Published:2020-10-14

摘要/Abstract

摘要： 体内雌激素水平下降是引起骨质疏松的重要因素, 用雌激素治疗绝经后妇女的骨质疏松症(osteoporosis,OP)会引发乳腺癌, 因而人们使用选择性雌激素受体调节剂(selective estrogen receptormodulator,SERMs)来治疗绝经后妇女OP。SERMs可选择的作用于雌激素受体(estrogen receptor,ER), 抑制骨吸收、破骨细胞形成而阻止骨质流失。SERMs 是目前比较理想的治疗绝经后妇女OP 的药物。本文就SERMs 的作用机制及其治疗OP 效果进行综述, 并探讨SERMs 治疗绝经后OP的前景和意义。

关键词: 选择性雌激素受体调节剂, 骨质疏松症, 雌激素受体

Abstract: The reduction of estrogen is the main cause that leads to osteoporosis(OP). Selective estrogen receptor modulators (SERMs) have been developed and applied for the treatment of postmenopausal OP because breast cancer is triggered while using estrogen to cure OP. SERMs selectively act on the estrogen receptor that could inhibit the absorbability of bone and the formation of osteoclast, this manner may prevent the loss of bone mineral density. Presently, it is considered that SERMs were the ideal drugs for curing postmenopausal OP. In the paper, the functional mechanism of SERMs and their effects on curing OP were summarized, the scientific significance and perspective for application of SERMs on the therapy of postmenopausal OP were discussed.

Key words: selective estrogen receptor modulator, osteoporosis, estrogen receptor

中图分类号:

R965.2
R681

李孟森, 周升, 李刚. 选择性雌激素受体调节剂的作用机制及其治疗绝经后骨质疏松症的研究现状[J]. 中国临床药理学与治疗学, 2008, 13(2): 213-219.

LI Meng-Sen, ZHOU Sheng, LI Gang. Advances on mechanisms of selective estrogen receptor modulators and their therapy of postmenopausal osteoporosis[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(2): 213-219.

参考文献

[1] Eichner SF, Lloyd KB, Timpe EM. Comparing therapies for postmenopausal osteoporosis prevention and treatment[J]. Ann Pharmacother, 2003, 37(5):711-724.
[2] Bone HG, Hosking D, Devogelaer JP, et al. Ten years experience with alendronate for osteoporosis in postmenopausal Women[J]. N Engl J Med, 2004, 350(12):1189-1199.
[3] Gennari L, Becherini L, Falchetti A, et al. Genetics of osteoporosis:role of steroid hormone receptor gene polymorphisms[J]. J Steroid Biochem Mol Biol, 2002, 81(1): 1-24.
[4] Russo IH, Russo J. Role of hormones in mammary cancer initiation and progression[J]. J Mammary Gland Biol Neoplasia, 1998, 3(1):49-61.
[5] Di Leo A, Messa C, Cavallini A, et al. Estrogens and colorectal cancer[J]. Curr Drug Targets Immune Endocr Metabol Disord, 2001, 1(1):1-12.
[6] Pujol P, Rey JM, Nirde P, et al. Differential expression of estrogen receptor-alpha and-beta messenger RNAs as a potential marker of ovarian carcinogenesis[J]. Cancer Res, 1998, 58(23):5367-5373.
[7] Cyr M, Calon F, Morissette M, et al. Estrogenic modulation of brain activity:Implications for schizophrenia and Parkinson' s disease[J]. J Psychiatry Neurosci, 2002, 27(1):12-27.
[8] Robinson-Rechavi M, Escriva GH, Laudet V. The nuclear receptor superfamily[J]. J Cell Sci, 2003, 116(4):585-586.
[9] Gronemeyer H, Gustafsson JA, Laudet V. Principles for modulation of the nuclear receptor superfamily[J]. Nat Rev Drug Discov, 2004, 3(11):950-964.
[10] Turner RT, Riggs BL, Spelsberg TC. Skeletal effects of estrogen[J]. Endocr Rev, 1994, 15(3):275-300.
[11] Mora S, Kershner DW, Vigilance CP, et al. Coronary artery disease in postmenopausal women[J]. Curr Treat Options Cardiovasc Med, 2001, 3(1):67-79.
[12] Adami HO, Bergstrom R, Weiderpass E, et al. Risks of breast and endometrial cancer after estrogen and estrogenprogestin replacement[J]. Cancer Causes Control, 1999, 10(4):253-260.
[13] Anthony M, Williams J K, Dunn BK. What would be the properties of an ideal SERM[J]? Ann N Y Acad Sci, 2001, 949:261-278.
[14] Conzen SD. Current status of selective estrogen receptor modulators (SERMs)[J]. Cancer J, 2003, 9(1):4-14.
[15] Labrie F, Labrie C, Belanger L, et al. EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium[J]. J Steriod Biochem Mol Biol, 1999, 69(1-6):51-84.
[16] Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer[J]. N Engl JMed, 1992, 326(13): 852-856.
[17] Pace P, Taylor J, Suntharalingam S, et al. Human estrogen receptor beta binds DNA in a manner similar to and dimerizes with estrogen receptor alpha[J]. J Biol Chem, 1997, 272(41):25832-25838.
[18] Katzenellenbogen BS, Katzenellenbogen JA. Enhanced: defining the “S” in SERMs[J]. Science, 2002, 295(5564):2380-2381.
[19] Pennisi E. Differing roles for estrogen' s two receptors[J]. Science, 1997, 277(5331):1439.
[20] MacGregor Schafer JI, Liu H, Tonetti DA, et al. The Interaction of raloxifene and the active metabolite of the antiestrogen EM-800(SC 5705)with the human estrogen receptor[J]. Cancer Res, 1999, 59(17):4308-4313.
[21] 张杰. 选择性ER 调节剂[J]. 中国新药杂志, 2000, 9(10):676-680.
[22] Levenson AS, Catherino WH, Jordan VC. Estrogenic activity is increased for an antiestrogen by a natural mutation of the estrogen receptor[J]. J Steroid Biochem Mol Biol, 1997, 60(5-6):261-268.
[23] Kuiper GGJM, Carlsson B, Grandien K, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta[J]. Endocrinology, 1997, 138(3):863-870.
[24] Pike AC, Brzozowski AM, Hubbard RE, et al. Structure of the ligand2 binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist[J]. EMBO J, 1999, 18(17):4608-4618.
[25] Hall JM, McDonnell DP. The estrogen receptor beta-isoform (ER beta)of the human estrogen receptor modulates ER alpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens[J]. Endocrinology, 1999, 140(12):5566-5578.
[26] Paech K, Webb P, Kuiper GGJM, et al. Differential ligand activation of estrogen receptors ERαand ERβ at AP1 sites[J]. Science, 1997, 277(5331):1508-1510.
[27] Shang Y, Brown M. Molecular determinants for the tissue specificity of SERMs[J]. Science, 2002, 295(5564): 2465-2468.
[28] 贵春山, 沈建华, 罗小民, 等. ER 和选择性ER 调节剂的研究进展[J]. 中国药物化学杂志, 2005, 15(5):313-320.
[29] Wu H, Chen Y, Liang J, et al. Hypomethylation-linked activator of PAX2 mediates tamoxifen-stimulated endometrical carcinogenesis[J]. Nature, 2005, 438(7070):981-987.
[30] Rosen CJ. Postmenopausal osteoporosis[J]. N Engl J Med, 2005, 353(6):595-603.
[31] Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women:results from the MORE randomized trial[J]. JAMA, 1999, 281(23):2189-2197.
[32] 张小玉, 陆重琳, 刘社兰, 等. 选择性ER 调节剂雷洛昔芬阻止去卵巢大鼠骨丢失的机制[J]. 中华老年医学杂志, 2004, 23(6):402-405.
[33] Riggs BL, Hartmann LC. Selective estrogen-receptor modulators-Mechanisms of action and application to clinical cractice[J]. N Engl J Med, 2003, 348(12):618-629.
[34] Perry MJ, Gujra S, Whitworth T, et al. Tamoxifen stimulates cancellous bone formation in long bones of female mice[J]. Endocrinology, 2005, 146(3):1060-1065.
[35] Barham M, Riggs BL, Hartmann LC. Selective estrogenreceptor modulators[J]. N Engl J Med, 2003, 348(22):2259.
[36] Gennari L, Merlotti D, Valleggi F, et al. Selective estrogen receptor modulators for postmenopausal osteoporosis: current state of development[J]. Drugs Aging, 2007, 24(5):361-379.
[37] Stump AL, Kelley KW, Wensel TM. Bazedoxifene:A Third-generation selective estrogen receptor modulator for treatment of postmenopausal osteoporosis[J]. Ann Pharmacother, 2007, 41(5):833-839.
[38] Acconcia F, Barnes CJ, Kumar R. Estrogen and tamoxifen induce cytoskeletal remodeling and migration in endometrial cancer cells[J]. Endocrinology, 2006, 147(3): 1203-1212.
[39] Nalbandian G, Paharkova-Vatchkova V, Mao A, et al. The selective estrogen receptor modulators, tamoxifen and raloxifene, impair dendritic cell differentiation and activation[J]. J Immunol, 2005, 175(4):2666-2675.
[40] Mao A, Paharkova-Vatchkova V, Hardy J, et al. Estrogen selectively promotes the differentiation of dendritic cells with characteristics of langerhans Cells[J]. J Immunol, 2005, 175(8):5146-5151.
[41] Gold DT, Silverman SL. Do estrogen or selective estrogen receptor modulators improve quality of life for women with postmenopausal osteoporosis[J] ? Curr Osteoporos Rep, 2007, 5(1):3-7.
[42] 吉庆刚, 谢毓元. 选择性ER 调节剂的研究与开发[J]. 药学进展, 2005, 29(8):344-349.