Abstract：
Hydroxysteroid (17beta) dehydrogenase type 1 (HSD17B1) is an enzyme that converts estrone to estradiol, while adenomyosis is an estrogen-dependent disease with poorly understood pathophysiology. In the present study, we show that mice universally over-expressing human estrogen biosynthetic enzyme HSD17B1 (HSD17B1TG mice) present with adenomyosis phenotype, characterized by histological and molecular evaluation. The first adenomyotic changes with endometrial glands partially or fully infiltrated into the myometrium appeared at the age of 5.5 months in HSD17B1TG females and became more prominent with increasing age. Preceding the phenotype, increased myometrial smooth muscle actin positivity and increased amount of glandular myofibroblast cells were observed in HSD17B1TG uteri. This was accompanied by transcriptomic upregulation of inflammatory and estrogen signaling pathways. Further, the genes upregulated in the HSD17B1TG uterus were enriched with genes previously observed to be induced in the human adenomyotic uterus, including several genes of the NFKB pathway. A 6-week-long HSD17B1 inhibitor treatment reduced the occurrence of the adenomyotic changes by 5-fold, whereas no effect was observed in the vehicle-treated HSD17B1TG mice, suggesting that estrogen is the main upstream regulator of adenomyosis-induced uterine signaling pathways. HSD17B1 is considered as a promising drug target to inhibit estrogen-dependent growth of endometrial disorders. The present data indicate that HSD17B1 over-expression in TG mice results in adenomyotic changes reversed by HSD17B1 inhibitor treatment and HSD17B1 is, thus, a potential novel drug target for adenomyosis.
摘要：
羟基类固醇（17β）脱氢酶1型（HSD17B1）是一种将雌酮转化为雌二醇的酶，而子宫腺肌病是一种雌激素依赖性疾病，对其病理生理学了解甚少。在本研究中,我们显示，小鼠普遍过度表达人雌激素生物合成酶HSD17B1（HSD17B1TG小鼠）呈现子宫腺肌病表型，以组织学和分子评估为特征。在HSD17B1TG雌性中，部分或完全浸润到子宫肌层的子宫内膜腺体的第一个腺体变化出现在5.5个月大时，并且随着年龄的增长而变得更加突出。在表型之前，在HSD17B1TG子宫中观察到子宫肌层平滑肌肌动蛋白阳性增加和腺成肌纤维细胞数量增加。这伴随着炎症和雌激素信号通路的转录组上调。Further,在HSD17B1TG子宫中上调的基因富含先前观察到的在人子宫中诱导的基因，包括NFKB途径的几个基因。为期6周的HSD17B1抑制剂治疗可将腺病毒变化的发生减少5倍，而在媒介物处理的HSD17B1TG小鼠中没有观察到效果，提示雌激素是子宫腺肌病诱导的子宫信号通路的主要上游调节因子。HSD17B1被认为是抑制子宫内膜疾病雌激素依赖性生长的有前途的药物靶标。目前的数据表明，TG小鼠中HSD17B1的过表达导致HSD17B1抑制剂治疗逆转的腺病毒变化，HSD17B1是，因此，子宫腺肌病的潜在新药物靶点。
