title: Growth differentiation factor 8 down-regulates pentraxin 3 in human granulosa cells.
abstract: Growth differentiation factor 8 (GDF8), also known as myostatin, is highly expressed in the mammalian musculoskeletal system and plays critical roles in the regulation of skeletal muscle growth. Though not exclusively expressed in the musculoskeletal system, the expression and biological function of GDF8 has never been examined in the human ovary. Pentraxin 3 (PTX3) plays a key role in the assembly of extracellular matrix, which is essential for cumulus expansion, ovulation and in vivo fertilization. The aim of this study was to investigate GDF8 expression and function in human granulosa cells and to examine its underlying molecular determinants. An established immortalized human granulosa cell line (SVOG), granulosa cell tumor cell line (KGN) and primary granulosa-lutein cells were used as study models. We now demonstrate for the first time that GDF8 is expressed in human granulosa cells and follicular fluid. All 16 follicular fluid samples tested contained GDF8 protein at an average concentration of 3 ng/ml. In addition, GDF8 treatment significantly decreased PTX3 mRNA and protein levels. These suppressive effects, along with the induction of SMAD2/3 phosphorylation, were abolished by co-treatment with the ALK4/5/7 inhibitor SB431542. Knockdown of ALK5, ACVR2A/ACVR2B or SMAD4 reversed the effects of GDF8-induced PTX3 suppression. These results indicate that GDF8 down-regulates PTX3 expression via ACVR2A/ACVR2B-ALK5-mediated SMAD-dependent signaling in human granulosa cells. These novel findings support a potential role for GDF8 in the regulation of follicular function, likely via autocrine effects on human granulosa cells.
authors: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors: Hsun-Ming
authors: HM
authors: Chang
authors: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada; Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
authors: Lanlan
authors: L
authors: Fang
authors: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors: Jung-Chien
authors: JC
authors: Cheng
authors: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors: Christian
authors: C
authors: Klausen
authors: Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
authors: Ying-Pu
authors: YP
authors: Sun
authors: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada. Electronic address: peter.leung@ubc.ca.
authors: Peter C K
authors: PC
authors: Leung
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D002097:C-Reactive Protein / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D004149:Dioxoles / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D015571:Follicular Fluid / Q000378:metabolism; D006107:Granulosa Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D055435:Myostatin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D000683:Serum Amyloid P-Component / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D000099153:Pentraxins
chemical_list: D001549:Benzamides; D002097:C-Reactive Protein; D004149:Dioxoles; D055435:Myostatin; D000683:Serum Amyloid P-Component; D051785:Smad Proteins; D000099153:Pentraxins; C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; C525911:MSTN protein, human
keywords: ALK5; GDF8; Human granulosa cell; Pentraxin 3; SMAD