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 MMP-2 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 TGFβ-induced responses. In summary, our results demonstrate that endometriotic cells showed reduced responsiveness upon TGFβ 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.