Effects of 17β-HSD2 inhibition in bones on osteoporosis based on an animal rat model
Effects of 17β-HSD2 inhibition in bones on osteoporosis based on an animal rat model
复制标题
基于动物大鼠模型的 17β-HSD2 抑制对骨质疏松症的影响
DOI：
10.1016/j.jsbmb.2019.105405
复制
发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Vollmer G
中科院分区：
文献类型：
--
作者：
Müller ST;Pählig S;Merabet A;Abdelsamie AS;van Koppen CJ;Marchais-Oberwinkler S;Hartmann RW;Zierau O;Vollmer G
激素替代疗法是一种可行的选择，以保护骨从绝经后骨质疏松症。然而，全身性升高的雌激素水平是不利的，因为在其他器官中存在有害副作用的风险。本研究的基本原理是靶向雌二醇（E2）和睾酮（T）代谢中的关键酶，以器官特异性方式增加E2水平，从而避免全身性E2水平增加的缺点。17 β-羟基类固醇脱氢酶（17β-HSD 2）在骨中表达，催化E2和T氧化为雌酮（E1）和雄烯二酮。我们推测抑制17β-HSD 2会导致表达该酶的器官中E2和T水平升高。因此，我们可以直接使用E2的益处，或者在不影响全身水平的情况下，在骨骼中芳构化成E2后使用T的益处。我们首次测试了新型且有效的17β-HSD 2抑制剂化合物24（C24），以探索17β-HSD 2抑制在卵巢切除术（ovx）诱导的骨丢失大鼠模型中的治疗潜力。我们单独测试了抑制剂，并与低剂量雌激素补充剂一起测试了绝经后情况下的雌激素水平。雌性成年Wistar-Hannover大鼠每天单独或在补充苯甲酸雌二醇（E2 B）的情况下，以2、10、50 mg C24/kg体重的剂量给药8周，以减轻OVX诱导的骨丢失。OVX安慰剂和假手术动物作为阴性和阳性对照。对实验的有效性和安全性方面进行了评价：分析骨以评价骨保护作用，并分析子宫以评价潜在的、不需要的E2介导的副作用。我们观察到C24具有良好的生物利用度，因为测得的血浆浓度非常高，ovx C24-high组的组平均值高达15，412 nM。组织形态计量学分析和体内和体外μCT显示，使用的最低抑制剂浓度具有显著的骨保护作用。无论血浆浓度如何，均未观察到子宫增殖效应。这些结果支持了我们的方法，细胞内靶向E2和T代谢的关键酶，以器官特异性方式增加E2和T水平。
Hormone replacement therapy is a viable option to protect bone from postmenopausal osteoporosis. Systemically elevated estrogen levels, however, are disadvantageous because of the risk of harmful side effects in other organs. The rationale of the study presented here is to target a key enzyme in estradiol (E2) and testosterone (T) metabolism to increase E2 levels in an organ-specific manner, thereby avoiding the disadvantages of systemically increased E2 levels. The 17ß-hydroxysteroid dehydrogenase (17β-HSD2), which ise.g.expressed in bone, catalyzes the oxidation of E2 and T into estrone (E1) and androstenedione. We postulate that inhibiting 17β-HSD2 should lead to elevated E2 and T levels in organs expressing the enzyme. Therefore, we can use the benefits of E2 directly, or those of T following aromatization into E2, in the bone without affecting systemic levels. We tested for the first time, the novel and potent 17β-HSD2 inhibitor, compound24(C24), to explore the therapeutic potential of a 17β-HSD2 inhibition in an ovariectomy (ovx)-induced rat model of bone loss. We tested the inhibitor alone and, together with low dose estrogen supplementation to model estrogen levels in the postmenopausal situation. Female mature Wistar-Hannover rats were treated for 8 weeks with doses of 2, 10, 50 mg C24per kg body weight per day alone or in the presence of estradiol benzoate (E2B) supplementation to alleviate ovx-induced bone loss. Ovx placebo and sham operated animals served as negative and positive controls. The experiment was evaluated regarding aspects of efficacy and safety: Bone was analyzed to evaluate bone protective effects, and uterus for potential, unwanted E2-mediated side effects. We observed a good bioavailability of C24as very high plasma concentrations were measured, up to a group mean of 15,412 nM for theovx C24-highgroup. Histomorphometrical analyses andin vivo&ex vivoμCT revealed significant bone protective effects for the lowest inhibitor concentration used. Irrespective of the plasma concentration, no proliferative effects in the uterus could be observed. These results support our approach of intracellular targeting key enzymes of E2 and T metabolism to increase E2 and T levels in an organ specific manner.
登录
查看更多内容
影响因子：
--
作者：
Hewitt, SC;Deroo, BJ;Korach, KS
通讯作者：
Korach, KS
大鼠 17 β-羟基类固醇脱氢酶 2 型的克隆以及大鼠 1 型和 2 型酶的组织分布和催化活性的表征。
影响因子：
4.8
作者：
L. Akinola;M. Poutanen;R. Vihko
通讯作者：
R. Vihko
影响因子：
2.4
作者：
Mueller, Sebastian T.;Keiler, Annekathrin M.;Bernhardt, Ricardo
通讯作者：
Bernhardt, Ricardo
DOI：
10.1016/j.phymed.2017.08.001
发表时间：
2017-10-15
期刊：
Phytomedicine : international journal of phytotherapy and phytopharmacology
影响因子：
--
作者：
Keiler AM;Helle J;Bader MI;Ehrhardt T;Nestler K;Kretzschmar G;Bernhardt R;Vollmer G;Nikolić D;Bolton JL;Pauli GF;Chen SN;Dietz BM;van Breemen RB;Zierau O
通讯作者：
Zierau O
17β-羟基类固醇脱氢酶 2 型抑制剂对去卵巢食蟹猴骨强度的影响。
影响因子：
1.9
作者：
Bagi Cm;J. Wood;D. Wilkie;B. Dixon
通讯作者：
B. Dixon