Validation of 17beta-HSD2 inhibition as potential approach for the prevention of osteoporosis: comparison of in vivo efficacy and safety between a 17beta-HSD2 inhibitor and a specifically targeting bone 17beta-HSD2 inhibitor

卵巢雌激素分泌的停止是绝经后妇女骨质疏松改变的主要原因。保持雌激素水平的增加对治疗和预防骨质疏松症是有益的。这是这一建议的工作假说，这可以通过抑制17β-羟基类固醇脱氢酶2(17β-HSD2)来实现。已经描述了17β-HSD2的有效和选择性抑制剂。这种酶在骨骼和其他器官如乳房和子宫内膜中都有表达。抑制17β-HSD2会增加骨骼局部的E2水平。然而，由于这种酶的分布更广泛，在所有表达这种酶的组织中，E2水平也会升高，因此，从理论上讲，会造成副作用(乳腺癌或子宫内膜增生)的风险。骨骼含有很高的矿物含量(羟基磷灰石)，这使得它们特别容易成为带负电荷的物质的靶标。该项目的目标是：1.通过将骨载体(带负电荷)与先前描述的活性17β-HSD2抑制剂连接起来，优化17β-HSD2抑制剂的结构，以确保骨的特异性。新设计的带有骨载体的化合物在血浆中足够稳定，以保持完整的骨吸收，载体部分应被内源性酯酶在骨中切割，以释放活性的17β-HSD2抑制物。2.利用去势诱导的骨质疏松大鼠模型，在体内评价两种化合物的预防效果。这些化合物包括a)一种可用的、先前描述的没有骨靶向载体的活性17β-HSD2抑制剂，以及相同的具有骨载体的17β-HSD2抑制剂，将在点1下确定，最后3.通过在使用这两种抑制剂后分析关键组织(乳腺、子宫内膜)来评估该方法的安全性。作为一个结果，我们期待17β-HSD2作为治疗和预防绝经后骨质疏松症的有前景的靶点的验证，并识别潜在的缺陷。

Cessation of ovarian estrogen production represents a major cause for osteoporotic changes in the bone of postmenopausal women. Maintenance of increased levels of estradiol (E2), the most potent estrogen locally in bone rather than systemically, is beneficial for the treatment and prevention of osteoporosis. It is the working hypothesis of this proposal that this could be achieved by 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD2) inhibition. Potent and selective inhibitors of 17beta-HSD2 have already been described. This enzyme is expressed in bones and in other organs like breast and endometrium. Inhibition of 17beta-HSD2 will increase E2 levels locally in bones. However, due to the more general distribution of this enzyme, E2 levels will also be elevated in all tissues where the enzyme is expressed and therefore, theoretically, pose a risk for side-effects (breast cancer or endometrial hyperplasia). Bones have a high mineral content (hydroxyapatite), which make them specifically targetable by negatively charged substances. The goals of the proposed project are: 1. to optimize the structure of the 17beta-HSD2 inhibitors, by linking a bone carrier (bearing negative charges) to a previously described active 17beta-HSD2 inhibitor to assure bone specificity. The newly designed compound with bone carrier should be stable enough in plasma to stay intact for uptake onto bone and the carrier moiety should be cleaved in bone by endogenous esterases to liberate the active 17beta-HSD2 inhibitor, 2. to evaluate the efficacy of 2 compounds in vivo in a preventive setting using the castration-induced osteoporosis rat model. The compounds comprise a) an available, previously described active 17beta-HSD2 inhibitor without bone targeting carrier, as well as the same 17beta-HSD2 inhibitor with bone carrier, to be identified under point 1 and finally 3. to assess the safety aspect of this approach by analyzing critical tissues (mammary gland, endometrium) following administration of both inhibitors. As an outcome, we expect the validation of 17beta-HSD2 as promising target for the treatment and prevention of postmenopausal osteoporosis and the identification of potential drawbacks.