Role of transforming growth factor β?1 in the pathogenesis of pelvic organ prolapse: A potential therapeutic target

摘要

The present study aimed to reveal the metabolic alterations of the extracellular matrix?(ECM) in uterosacral ligament?(USL) with pelvic organ prolapse?(POP) and to explore the role of transforming growth factor?β1?(TGF?β1) in pathogenesis of POP. For this purpse, 60?participants who underwent hysterectomy for benign indications were enrolled, 30?of which had symptomatic POP?(grade?II, III or?IV) and composed the POP group, and the other 30 had asymptomatic POP?(grade?I or less) and served as the controls. Collagen fibers, elastin,matrix metalloproteinase?(MMP)?2/9, tissue inhibitor of matrix metalloproteinases?(TIMP)?2 and TGF?β1 were examined by Masson's trichrome staining, immunohistochemistry and RT-qPCR using USL biopsies. In?vitro, human USL fibroblasts?(hUSLFs) were primary cultured, pre-treated with recombinant TGF?β1?(0, 5, or 10?ng/ml) and then subjected to cyclic mechanical stretching?(CMS; 0?or 5,333?με strain). Changes in the expression levels of collagen?type?I/III, elastin, TIMP?2, MMP?2/9 and Smad were detected. Our results revealed that at the tissue level, the expression of collagen fibers, elastin, TIMP?2 and TGF?β1 was significantly reduced in the POP group, while the activities of MMP?2/9 were significantly upregulated, compared with the control group. Statistical analysis indicated that the mRNA expression of TGF?β1 inversely correlated with the severity of POP partially. Our in?vitro experimental data demonstrated that a CMS of 5333?με strain promoted the degradation of ECM proteins, inhibited the synthesis of TIMP?2, and upregulated the proteolytic activities of MMP?2/9. Pre-treatment with TGF?β1 attenuated the loss of ECM by stimulating the synthesis of TIMP?2 and inhibiting the activities of MMP?2/9 through the TGF?β1/Smad3 signaling pathway. On the whole, our data indicate that the reduced anabolism and increased catabolism of ECM proteins in USL are the pathological characteristics of POP. TGF?β1 not only has a specific value in predicting the severity of POP, but should also be considered as a novel therapeutic target for POP.