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

Abstract

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.

Search for aglycone isoflavone from soybean as candidate for pelvic organ prolapse treatment: In silico study of TGF-β1, Hsp70, and Bcl-xl signals

“…TGF-b1 pathway is considered as the newest therapeutic target for pelvic organ prolapse [6]. As for TGF-b1 signal, firstly, TGF-b1 will interact with TGF-b type II (TGF-bII) receptor and then with TGF-b type I (TGF-bI) receptor.…”

“…The role of TGF-b in pelvic organ prolapse is still unclear. In the case of pelvic organ prolapse, the expressions of mRNA and TGF-b1 protein are correlated negatively with the level of pelvic organ prolapse [5,6]. Other researcher found that TGF-b1 expressions in uterosacral ligament were almost similar between pelvic organ prolapse and the control [7].…”

“…This is presumably due to the downregulation of TGF-b receptor [8]. In the in vitro test using the strain model of extracellular matrix degradation, TGF-b1 application can inhibit the loss of extracellular matrix through TGF-b1/ Smad3 signals [6]. In addition, oxidative stress was involved in the TGF-b change in pelvic organ prolapse [9].…”

Role of Connective Tissue Dysfunction Markers in Surgical Treatment of Pelvic Prolapse

“…Активность перечисленных генов определялась путем анализа периферической крови, доступность этого материала для анализа делает диагностику в большей степени простой и быстрой. В качестве еще одного субстрата для исследования могут выступать крестцово-маточные связки [42][43][44][45][46][47][48][49][50][51] и гораздо реже биоптат стенки влагалища [48,49,52,53]. Зачастую именно крестцово-маточные связки вовлечены в патогенез синдрома слабости тазового дна, поэтому именно эти структуры изучаются на наличие нарушений, связанных с дезорганизацией соединительной ткани [54].…”

“…К маркерам, связанным с окислительным стрессом и ПТО, можно отнести 8-гидроксидезоксигуанозин и 4-гидроксиноненал [42], фосфатидилинозитол-3-киназу/протеинкиназу В [43], митофузин 2 [44]. Выделяют и другие маркеры: уровень экспрессии генов COMP, NDP и SNAI2 [46], HOXA11 и MMP2 [54], концентрации глутатионпероксидазы 1 [45], флавопротеинов переноса электрона, аполипопротеина A I , актина, трансгелина, кофилина 1, циклофилина A, миозина и галектина 1 [47], трансформирующего фактора роста бета-1 [48]. Все эти предикторы определялись с помощью полимеразной цепной реакции (ПЦР).…”