Down-regulation of endometrial matrix metalloproteinase-3 and -7 expression in vitro and therapeutic regression of experimental endometriosis in vivo by a novel nonsteroidal progesterone receptor agonist, tanaproget
Down-regulation of endometrial matrix metalloproteinase-3 and -7 expression in vitro and therapeutic regression of experimental endometriosis in vivo by a novel nonsteroidal progesterone receptor agonist, tanaproget
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DOI：
10.1210/jc.2005-2024
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发表时间：
2006-04-01
影响因子：
5.8
通讯作者：
Osteen, KG
中科院分区：
文献类型：
--
作者：
Bruner-Tran, KL;Zhang, ZM;Osteen, KG
背景：子宫内膜异位症，即子宫内膜组织在子宫外生长，主要是一种雌激素依赖性疾病。相反，在怀孕期间或治疗期间暴露于孕酮已被证明对某些患有这种疾病的妇女有益。然而，最近的研究表明，子宫内膜异位症的存在损害了在位子宫内膜的能力，以响应内源性pegesteron.Objective：降低孕激素的反应性导致子宫内膜基质金属蛋白酶（MMPs）在月经周期的分泌期妇女子宫内膜的表达增加。尽管周期性MMP表达对子宫内膜的生长和重塑至关重要，但孕酮下调MMP的失败可能会损害着床并促进子宫内膜异位症的侵袭性建立。在本研究中，我们检测了一种新开发的孕激素受体（PR）激动剂tanaproget（TNPR）在体外下调子宫内膜MMP表达和在体内消退实验性子宫内膜异位症的能力。我们研究了TNPR在体外下调子宫内膜MMP表达的能力，与天然孕酮和两种目前上市的合成甾体孕激素相比。使用人/小鼠子宫内膜异位症模型，我们还测试了TNPR在体内使由孕酮敏感性降低的组织建立的异位病变消退的能力。结果：TNPR在体外有效地下调MMP表达，并诱导由子宫内膜异位症患者的组织建立的疾病小鼠的病变显著减少。鉴于最近报道的TNPR的临床前药理学特征，有必要进一步开发该化合物用于治疗子宫内膜异位症。
Context: Endometriosis, the growth of endometrial tissue outside the uterus, is principally an estrogen-dependent disease. In contrast, exposure to progesterone during pregnancy or therapeutically has been shown to provide benefit to some women with this disease. However, recent research suggests that the presence of endometriosis impairs the capacity of the eutopic endometrium to respond to endogenous progesterone.Objective: Reduced progesterone responsiveness results in an elevated endometrial expression of matrix metalloproteinases ( MMPs) during the secretory phase of the menstrual cycle in women with endometriosis. Although cyclic MMP expression is critical for endometrial growth and remodeling, the failure of progesterone to downregulate MMPs may impair nidation and promote the invasive establishment of endometriosis. In the current study we examined the ability of a newly developed progesterone receptor ( PR) agonist, tanaproget (TNPR), to down-regulate endometrial MMP expression in vitro and regress experimental endometriosis in vivo.Setting: This study was performed at a university-based medical center.Participants: Asymptomatic volunteers and patients with endometriosis were studied.Main Outcome Measures: We examined the ability of TNPR to down-regulate endometrial MMP expression in vitro compared with that of natural progesterone and two currently marketed synthetic steroidal progestins. Using a human/mouse model of endometriosis, we also tested the in vivo ability of TNPR to regress ectopic lesions established by tissues with reduced progesterone sensitivity.Results: TNPR effectively down-regulated MMP expression in vitro and induced significant reduction of lesions in mice with disease established by tissues from endometriosis patients.Conclusion: Given the positive preclinical pharmacological profile of TNPR that has recently been reported, additional development of this compound for the treatment of endometriosis is warranted.