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Activin A Modulates Betaglycan Shedding via the ALK4-SMAD3-Dependent Pathway in Endometriotic Cells

Affiliation
Faculty of Medicine, Center of Gynecology and Obstetrics, Justus-Liebig-University, D-35392 Giessen, Germany
Mwaura, Agnes N.;
Affiliation
Faculty of Medicine, Center of Gynecology and Obstetrics, Justus-Liebig-University, D-35392 Giessen, Germany
Riaz, Muhammad A.;
Affiliation
Faculty of Medicine, Center of Gynecology and Obstetrics, Justus-Liebig-University, D-35392 Giessen, Germany
Maoga, Jane B.;
ORCID
0000-0002-0049-5336
Affiliation
Department of Biochemistry, University of Nairobi, Nairobi P.O. Box 30197-00100, Kenya
Mecha, Ezekiel;
Affiliation
Department of Biochemistry, University of Nairobi, Nairobi P.O. Box 30197-00100, Kenya
Omwandho, Charles O. A.;
Affiliation
Institute for Veterinary Physiology and Biochemistry, School of Veterinary Medicine, Justus-Liebig-University, D-35392 Giessen, Germany
Scheiner-Bobis, Georgios;
Affiliation
Faculty of Medicine, Center of Gynecology and Obstetrics, Justus-Liebig-University, D-35392 Giessen, Germany
Meinhold-Heerlein, Ivo;
ORCID
0000-0001-5878-3050
Affiliation
Faculty of Medicine, Center of Gynecology and Obstetrics, Justus-Liebig-University, D-35392 Giessen, Germany
Konrad, Lutz

The TGF-β superfamily members, activins and inhibins, are mainly involved in cell proliferation, cell survival, invasion, immune surveillance, and lesion growth in endometriosis. Herein, we investigated the modulation of the TGF-β type III receptor (betaglycan or BG) by activin A and inhibin A in endometriosis in vitro. Often, BG undergoes ectodomain shedding releasing soluble BG (sBG) which frequently antagonizes TGF-β signaling. The effects of activin A on BG shedding and signaling pathways involved were evaluated with the inhibitors LY364947 and SIS3, siRNA knockdown in human endometrial cells (12Z, THESC, Ishikawa, and primary stromal cells) and were quantified with BG ELISAs. The effects of activin A and inhibin A on the secretion of MMP2 and MMP3 were analyzed using ELISAs. The effects of activin A on the BG expression were analyzed using RT-qPCR and western blot. The CCK-8 and BrdU assays were used to evaluate the effects of the recombinant BG on cell viability and proliferation. Activin A stimulation resulted in a significant time- and dose-dependent reduction in BG shedding, which was found to be activin A/ALK-4/SMAD3- but not SMAD2-dependent. Activin A increased the BG mRNA expression but had no effect on the protein expression. Likewise, inhibin A was found to block BG shedding. Activin A, but not inhibin A, significantly enhanced the secretion of MMP2 and MMP3. The recombinant BG had no effect on the viability and proliferation of endometriotic cells. Together, these observations support a novel role for activin A with BG in modulating the TGF-β superfamily ligands in endometrial cells in vitro.

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