title: Connective tissue growth factor mediates growth differentiation factor 8-induced increase of lysyl oxidase activity in human granulosa-lutein cells.
abstract: Lysyl oxidase (LOX) is an essential enzyme for the stabilization of the extracellular matrix (ECM) and the subsequent follicle and oocyte maturation. Currently, there is limited information pertaining to the regulation of LOX activity in human ovarian tissue. Growth differentiation factor 8 (GDF8) is a unique member of the transforming growth factor-β superfamily that is expressed in human granulosa cells and has important roles in regulating a variety of ovarian functions. The aim of the present study was to investigate the effects of GDF8 on the regulation of LOX expression and activity in human granulosa cells and to examine the underlying molecular determinants. An established immortalized human granulosa cell line (SVOG) and primary granulosa-lutein cells were used as study models. Using dual inhibition approaches (TGF-β type I inhibitor SB505124 and small interfering RNAs) and ChIP analyses, we have demonstrated that GDF8 up-regulated the expression of connective tissue growth factor (CTGF) through the activin receptor-like kinase 5-mediated SMAD2/3-SMAD4 signaling pathways. In addition, the increase in CTGF expression contributed to the GDF8-induced increase in LOX expression and activity. Our findings suggest that GDF8 and CTGF may play critical roles in the regulation of ECM formation in human granulosa cells.
authors.affiliation: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Hsun-Ming
authors.initials: HM
authors.lastname: Chang
authors.affiliation: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada; Department of Human Reproductive Medicine, Beijing Obstetrics and Gynaecology Hospital, Capital Medical University, Beijing 100026, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada; Department of Obstetrics and Gynaecology, E-DA Hospital, Kaohsiung 82445, Taiwan.
authors.forename: Pang-Pin
authors.initials: PP
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Jung-Chien
authors.initials: JC
authors.lastname: Cheng
authors.affiliation: Department of Human Reproductive Medicine, Beijing Obstetrics and Gynaecology Hospital, Capital Medical University, Beijing 100026, China.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Yang
authors.affiliation: 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.forename: Peter C K
authors.initials: PC
authors.lastname: Leung
mesh_terms: D052117:Benzodioxoles / Q000494:pharmacology; D002460:Cell Line; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008184:Luteal Cells / Q000378:metabolism*; D055435:Myostatin / Q000235:genetics / Q000378:metabolism*; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: C519132:2-(5-benzo(1,3)dioxol-5-yl-2-tert-butyl-3H-imidazol-4-yl)-6-methylpyridine hydrochloride; D052117:Benzodioxoles; C526317:CCN2 protein, human; D007093:Imidazoles; C525911:MSTN protein, human; D055435:Myostatin; D011725:Pyridines; D055513:Connective Tissue Growth Factor; D008249:Protein-Lysine 6-Oxidase
keywords: CTGF; GDF8; Human granulosa cell; LOX