Abstract
Granulosa cell-derived activins play important roles in the regulation of ovarian functions. To date, there is limited information pertaining to the intracellular regulation, assembly, and secretion of endogenous activin A in human granulosa cells. The aim of this study was to examine the effects of BMP4 and BMP7 on furin expression and activin A production as well as the underlying mechanisms of action in human granulosa cells. An established immortalized human granulosa cell line (SVOG) and primary granulosa-lutein cells were used as study models. Expression of inhibin subunits and furin as well as activin A accumulation were examined after exposure to recombinant human BMP4 or BMP7. A BMP type I receptor inhibitor (dorsomorphin), a furin inhibitor (Decanoyl-Arg-Val-Lys-Arg-chloromethylketone), and small interfering RNAs targeting SMAD4 and furin were used to verify the specificity of the effects and investigate potential mechanisms. The study was conducted in an academic center. Specific mRNA and protein levels were examined using real time qPCR and Western blot. Activin A levels were measured using enzyme immunoassay. Treatment with bone morphogenetic protein (BMP) 4 and BMP7 significantly increased furin mRNA and protein, inhibin βA mRNA, and activin A accumulation. Pre-treatment with dorsomorphin or SMAD4 knockdown reversed the stimulatory effects of BMP4 and BMP7 on furin and inhibin βA expression. In addition, furin knockdown or pre-treatment with a furin inhibitor attenuated the BMP4- and BMP7-induced accumulation of activin A. Recombinant BMP4 and BMP7 increase the production of bioactive mature activin A by up-regulating both the production and proteolytic processing of inhibin βA subunit in human granulosa cells. The enhancement of inhibin βA subunit processing is attributable to a SMAD-dependent up-regulation of its proprotein convertase, furin. These findings provide a potential mechanism by which theca cells can regulate neighboring granulosa cells in the ovary.
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: The Journal of Clinical Endocrinology & Metabolism
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
