Role of Betaglycan in TGF-β Signaling and Wound Healing in Human Endometriotic Epithelial Cells and in Endometriosis

Agnes N. Mwaura; Muhammad A. Riaz; Jane B. Maoga; Ezekiel Mecha; Charles O. A. Omwandho; Georgios Scheiner-Bobis; Ivo Meinhold-Heerlein; Lutz Konrad

doi:10.3390/biology11040513

Biology (Mar 2022)

Role of Betaglycan in TGF-β Signaling and Wound Healing in Human Endometriotic Epithelial Cells and in Endometriosis

Agnes N. Mwaura,
Muhammad A. Riaz,
Jane B. Maoga,
Ezekiel Mecha,
Charles O. A. Omwandho,
Georgios Scheiner-Bobis,
Ivo Meinhold-Heerlein,
Lutz Konrad

Affiliations

Agnes N. Mwaura: Center of Gynecology and Obstetrics, Faculty of Medicine, Justus-Liebig-University, Feulgenstr. 10-12, D-35392 Giessen, Germany
Muhammad A. Riaz: Center of Gynecology and Obstetrics, Faculty of Medicine, Justus-Liebig-University, Feulgenstr. 10-12, D-35392 Giessen, Germany
Jane B. Maoga: Center of Gynecology and Obstetrics, Faculty of Medicine, Justus-Liebig-University, Feulgenstr. 10-12, D-35392 Giessen, Germany
Ezekiel Mecha: Department of Biochemistry, University of Nairobi, Nairobi 00100, Kenya
Charles O. A. Omwandho: Reproductive Biochemistry, Kirinyaga University, Kerugoya 10300, Kenya
Georgios Scheiner-Bobis: Institute for Veterinary Physiology and Biochemistry, School of Veterinary Medicine, Justus-Liebig-University, D-35392 Giessen, Germany
Ivo Meinhold-Heerlein: Center of Gynecology and Obstetrics, Faculty of Medicine, Justus-Liebig-University, Feulgenstr. 10-12, D-35392 Giessen, Germany
Lutz Konrad: Center of Gynecology and Obstetrics, Faculty of Medicine, Justus-Liebig-University, Feulgenstr. 10-12, D-35392 Giessen, Germany

DOI: https://doi.org/10.3390/biology11040513
Journal volume & issue: Vol. 11, no. 4
p. 513

Abstract

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Endometriosis is characterized by the presence of ectopic endometrium most often in the pelvis. The transforming growth factor-beta (TGF-β) superfamily is also involved in the pathogenesis; however, betaglycan (BG, syn. TGF-β type III receptor) as an important co-receptor was not studied. We analyzed mainly BG ectodomain shedding because released soluble BG (sBG) often antagonizes TGF-β signaling. Furthermore, we studied the role of TGF-βs and BG in wound healing and evaluated the suitability of BG measurements in serum and endocervical mucus for non-invasive diagnosis of endometriosis. Evaluation of the BG shedding and signaling pathways involved as well as wound healing was performed with enzyme-linked immune assays (ELISAs), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), small interfering RNA (siRNA) knockdown, and scratch assays with human endometriotic epithelial cells. TGF-β1/2 stimulation resulted in a significant dose-dependent reduction in BG shedding in endometriotic cells, which was TGF-β/activin receptor-like kinase-5 (ALK-5)/mother against decapentaplegic homolog3 (SMAD3)- but not SMAD2-dependent. Inhibition of matrix metalloproteinases (MMPs) using the pan-MMP inhibitor GM6001 and tissue inhibitor of MMPs (TIMP3) equally attenuated BG shedding, signifying the involvement of MMPs in shedding. Likewise, recombinant BG moderately reduced the secretion of TGF-β1/2 and wound healing of endometriotic cells. TGF-β1 significantly enhanced the secretion of MMP2 and MMP3 and moderately promoted wound healing. In order to evaluate the role of BG in endometriosis, serum (n = 238) and mucus samples (n = 182) were analyzed. Intriguingly, a significant reduction in the levels of sBG in endocervical mucus but not in the serum of endometriosis patients compared to controls was observed. Collectively, these observations support a novel role for BG in the pathophysiology of endometriosis.

Published in Biology

ISSN: 2079-7737 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Biology (General)
Website: https://www.mdpi.com/journal/biology

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