Activation of Endoplasmic Reticulum Stress in Granulosa Cells from Patients with Polycystic Ovary Syndrome Contributes to Ovarian Fibrosis

• Published in: Scientific reports Vol. 7; no. 1; pp. 10824 - 13
• Main Authors: Takahashi, Nozomi, Harada, Miyuki, Hirota, Yasushi, Nose, Emi, Azhary, Jerilee MK, Koike, Hiroshi, Kunitomi, Chisato, Yoshino, Osamu, Izumi, Gentaro, Hirata, Tetsuya, Koga, Kaori, Wada-Hiraike, Osamu, Chang, R. Jeffrey, Shimasaki, Shunichi, Fujii, Tomoyuki, Osuga, Yutaka
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.09.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/51; 38; 38/71; 631/80/304; 64; 64/60; 692/308/575; 82; 82/51; 96; 96/21; Animals; Cells, Cultured; Collagen; Collagen - analysis; Disease Models, Animal; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Female; Fibrosis; Fibrosis - physiopathology; Granulosa cells; Granulosa Cells - pathology; Granulosa Cells - physiology; Growth factors; Humanities and Social Sciences; Humans; Mice; multidisciplinary; Ovaries; Ovary - pathology; Oxidative stress; Polycystic ovary syndrome; Polycystic Ovary Syndrome - complications; Polycystic Ovary Syndrome - pathology; Science; Science (multidisciplinary); Tauroursodeoxycholic acid; Thapsigargin; Transforming growth factor; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Tunicamycin
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-11252-7

Recent studies report the involvement of intra-ovarian factors, such as inflammation and oxidative stress, in the pathophysiology of polycystic ovary syndrome (PCOS), the most common endocrine disorder of reproductive age women. Endoplasmic reticulum (ER) stress is a local factor that affects various cellular events during a broad spectrum of physiological and pathological conditions. It may also be an important determinant of pro-fibrotic remodeling during tissue fibrosis. In the present study, we showed that ER stress was activated in granulosa cells of PCOS patients as well as in a well-established PCOS mouse model. Pharmacological inducers of ER stress, tunicamycin and thapsigargin, were found to increase the expression of pro-fibrotic growth factors, including transforming growth factor (TGF)-β1, in human granulosa cells, and their expression also increased in granulosa cells of PCOS patients. By contrast, treatment of PCOS mice with an ER stress inhibitor, tauroursodeoxycholic acid or BGP-15, decreased interstitial fibrosis and collagen deposition in ovaries, accompanied by a reduction in TGF-β1 expression in granulosa cells. These findings suggest that ER stress in granulosa cells of women with PCOS contributes to the induction of pro-fibrotic growth factors during ovarian fibrosis, and that ER stress may serve as a therapeutic target in PCOS.