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Old 06-12-2019, 05:12 AM
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rss Effects of 17?-HSD2 inhibition in bones on osteoporosis based on an animal rat model.

Effects of 17?-HSD2 inhibition in bones on osteoporosis based on an animal rat model.

J Steroid Biochem Mol Biol. 2019 Jun 08;:105405

Authors: Müller ST, Pählig S, Merabet A, Abdelsamie AS, van Koppen CJ, Marchais-Oberwinkler S, Hartmann RW, Zierau O, Vollmer G

Abstract
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 (17?-HSD2), which is e.g. expressed in bone, catalyzes the oxidation of E2 and T into estrone (E1) and androstenedione. We postulate that inhibiting 17?-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 17?-HSD2 inhibitor, compound 24 (C24), to explore the therapeutic potential of a 17?-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 C24 per 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 C24 as very high plasma concentrations were measured, up to a group mean of 15,412 nM for the ovx C24-high group. Histomorphometrical analyses and in vivo &ex vivo µCT 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.


PMID: 31185280 [PubMed - as supplied by publisher]



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