Lysyl oxidase (LOX) is a copper-dependent enzyme that maintains and stabilizes the extracellular matrix (ECM) by catalyzing the cross-linking of elastin and collagen. ECM within the ovarian follicle plays a crucial role in regulating follicular development and oocyte maturation. Bone morphogenetic protein 2 (BMP2) belongs to the BMP subfamily that has been shown to be involved in the process of ovarian folliculogenesis and luteal formation. To date, whether BMP2 regulates the activity of LOX during human follicular development remains to be elucidated. The aim of this study was to investigate the effect of BMP2 on the regulation of LOX expression and activity in human granulosa-lutein cells (hGL) and the underlying mechanisms. Using both primary and immortalized (SVOG cells) hGL cells, we demonstrated that BMP2 up-regulated the expression and activity of LOX and hence decreased the soluble collagens in cultured medium in hGL cells. Additionally, the mRNA and protein levels of two transcriptional factors, SNAIL and SLUG, were increased following cell exposure to BMP2. Knockdown of SNAIL, but not SLUG partially reversed BMP2-induced increases in LOX expression and activity. The BMP2-induced up-regulation of SNAIL expression was abolished by the pre-treatment with two BMP type I receptor inhibitors, dorsomorphin and DMH-1, but not SB431542. Moreover, knockdown of SMAD4 completely abolished BMP2-induced up-regulation of SNAIL expression and the subsequent increases in LOX expression and activity. Our results suggest that BMP2 increases LOX expression and activity via the up-regulation of SNAIL in hGL cells. These findings may provide insights into the functional role of BMP2 in the regulation of ECM formation during folliculogenesis.

中文翻译：

---

骨形态发生蛋白2通过人类颗粒-叶黄素细胞中蜗牛的上调来增加赖氨酰氧化酶的活性。

赖氨酰氧化酶（LOX）是一种铜依赖性酶，通过催化弹性蛋白和胶原蛋白的交联来维持和稳定细胞外基质（ECM）。卵巢卵泡内的ECM在调节卵泡发育和卵母细胞成熟中起着至关重要的作用。骨形态发生蛋白2（BMP2）属于BMP亚家族，已被证明与卵巢滤泡形成和黄体形成过程有关。迄今为止，BMP2是否在人类卵泡发育过程中调节LOX的活性仍有待阐明。这项研究的目的是研究BMP2对人颗粒-叶黄素细胞（hGL）中LOX表达和活性的调节作用及其潜在机制。使用原代和永生（SVOG细胞）hGL细胞，我们证明BMP2上调了LOX的表达和活性，从而降低了hGL细胞培养基中的可溶性胶原蛋白。此外，细胞接触BMP2后，两个转录因子SNAIL和SLUG的mRNA和蛋白质水平也增加了。击倒SNAIL，但不是SLUG可以部分逆转BMP2诱导的LOX表达和活性增加。BMP2诱导的SNAIL表达上调已通过使用两种BMP I型受体抑制剂dorsomorphin和DMH-1（但未使用SB431542）进行预处理而被取消。此外，敲除SMAD4完全消除了BMP2诱导的SNAIL表达上调，并随后消除了LOX表达和活性。我们的结果表明BMP2通过上调hGL细胞中SNAIL的表达来增加LOX表达和活性。