Transforming Growth Factor Betas Induce MMP-2 and MMP-9 Secretion via Smad-Dependent Signaling in Human Endometrial and Endometriotic Cells

Transforming growth factor-betas (TGF-βs) are elevated during menstruation and are involved in endometriosis. Similarly, matrix metalloproteinases like MMP2 are also highly expressed in patients with endometriosis. Expression of gelatinases, MMP-2 and MMP-9, is increased by TGF-βs. TGF-βs bind and activate receptor-mediated Smad proteins to mediate gene expression, however, also non-Smad signaling pathways participate in signal transduction of the TGF-βs. In this study, we found that of MMP-2 and MMP-9 is higher in stromal cells especially in endometriotic cells compared to epithelial cells. Treatment of endometrial and endometriotic stromal and epithelial cells with TGF-β1 or TGF-β2 decreased cell numbers, induced Smad3 phosphorylation, and enhanced MMP-2 and MMP-9 secretion in all cell lines studied. Whereas a TGF-β receptor inhibitor (TβRI) inhibitor completely blocked the TGF-β-induced reduction in cell numbers, Smad3 phosphorylation, and MMP2 and MMP-9 secretion, a Smad3 inhibitor completely blocked Smad3 phosphorylation but only partly blocked the other TGF-β-induced responses. In summary, our results demonstrate that endometriotic cells showed reduced responsiveness upon TGF-β treatment compared to endometrial cells and thus we suggest that endometriotic cells are more resistant to TGF-β signals which resemble characteristics of tumour cells. Also, we suppose that TGF-β-induced increase in MMP-2 and MMP-9 might contribute to endometriosis by increasing tissue breakdown during menstruation and increased invasiveness of the endometrial tissues during implantation at ectopic sites.