DHEA-induced ovarian hyperfibrosis is mediated by TGF-β signaling pathway

Abstract

BackgroundThe polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disorder with pathological mechanisms remain unclear. The following study investigates the ovarian hyperfibrosis forming via transforming growth factor-β (TGF-β) signaling pathway in Dehydroepiandrosterone (DHEA)- induced polycystic ovary syndrome (PCOS) rat model. We furthermore explored whether TGF-βRI inhibitor (SB431542) decreases ovarian fibrosis by counterbalancing the expression of fibrotic biomarkers.MethodsThirty female Sprague-Dawley rats were randomly divided into Blank group (n = 6), Oil group (n = 6), and Oil + DHEA-induced model group (n = 6 + 12). The model groups were established by subcutaneous injection of DHEA for 35 consecutive days. The 12 successful model rats were additionally divided in vehicle group (n = 6) and SB431542-treated group (n = 6). Vehicle group and SB431542-treated group, served as administration group and were intraperitoneally injected with DMSO and SB431542 for additional 14 consecutive days. Ovarian morphology, fibrin and collagen localization and expression in ovaries were detected using H&E staining, immunohistochemistry and Sirius red staining. The ovarian protein and RNA were examined using Western blot and RT-PCR.ResultsIn DHEA-induced ovary in rat, fibrin and collagen had significantly higher levels, while the main fibrosis markers (TGF-β, CTGF, fibronectin, a-SMA) were obviously upregulated. SB431542 significantly reduced the expression of pro-fibrotic molecules (TGF-β, Smad3, Smad2, a-SMA) and increased anti-fibrotic factor MMP2.ConclusionTGF-βRI inhibitor (SB431542) inhibits the downstream signaling molecules of TGF-β and upregulates MMP2, which in turn prevent collagen deposition. Moreover, ovarian hyperfibrosis in DHEA-induced PCOS rat model could be improved by TGF-βRI inhibitor (SB431542) restraining the transcription of accelerating fibrosis genes and modulating EMT mediator.Electronic supplementary materialThe online version of this article (10.1186/s13048-017-0375-7) contains supplementary material, which is available to authorized users.

Animal models of polycystic ovary syndrome: A review of hormone‐induced rodent models focused on hypothalamus‐pituitary‐ovary axis and neuropeptides

“…In the serum of DHEA-treated rats, LH levels were lower but T levels and LH/FSH ratio were higher than in control rats. 29,32 Serum levels of FSH, LH, E2, T, and P4 did not differ significantly between DHEAtreated and control mice. 28…”

“…DHEA‐treated rats showed irregular cycles, mainly remaining in estrus . In contrast, DHEA‐treated mice showed regular cycles …”

“…Ovary weight in postnatal DHEA‐treated rats was increased relative to that in controls; this was accompanied by ovarian cyst expansion, an increased number of cystic follicles, granular cell layer thinning, and thickening of the theca cell layer . DHEA‐treated mice showed normal ovary weight and growing follicle and CL populations …”

Is shear wave elastography relevant in the diagnosis of polycystic ovarian syndrome?

“…In recent studies, it has been envisaged that the stroma of the ovaries with PCOS is expected to be stiffened due to the increase of teca cells and the thickened fibrotic albuginea. In animal experiments, the presence of fibrosis in ovarian tissue was histopathologically revealed [37][38][39][40][41]. In humans, fibrosis in the ovarian tissue can be demonstrated non-invasively with elastography [10][11][12][13].…”

Erythropoietin Alleviates Burn-induced Muscle Wasting

“…Research of burn scars reports that TGF-β1 acts through the Smad protein system to activate genes related to fibrosis [36,37]. In addition, a downstream effector of TGF-β1, connective tissue growth factor (CTGF) was sustained increase in several fibrotic conditions [37][38][39][40][41] included burn scars to regulate ECM synthesis. However, scanty data investigated their pro-fibrotic role in skeletal muscle at the post-acute phase of burn and possible therapeutic agents.…”