Bone morphogenetic protein 2 increases lysyl oxidase activity via up-regulation of snail in human granulosa-lutein cells

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.