title: Differential activation of noncanonical SMAD2/SMAD3 signaling by bone morphogenetic proteins causes disproportionate induction of hyaluronan production in immortalized human granulosa cells.
abstract: Successful fertilization depends upon proper cumulus-oocyte complex (COC) expansion. Synthesized by hyaluronan synthases (HASs), hyaluronan forms the backbone of the COC matrix and plays a critical role in COC expansion. This study investigated the effects and mechanisms of ovarian BMPs on HAS expression and hyaluronan production in human granulosa cells. Treatment with BMP4, BMP6, BMP7 or BMP15 induced differing levels of noncanonical SMAD2/3, but equal levels of canonical SMAD1/5/8, phosphorylation which were mirrored by differing levels of HAS2 up-regulation and hyaluronan production. The effects of BMP4 and BMP15 on HAS2 mRNA were partially reversed by knockdown of SMAD3, and blocked by knockdown of SMAD2+SMAD3 or SMAD4. BMP4-induced SMAD2/3 phosphorylation and HAS2 mRNA up-regulation were mediated by both BMP and activin/transforming growth factor-β type I receptors. Our results suggest differential activation of noncanonical SMAD2/SMAD3 signaling by BMPs causes disproportionate induction of HAS2 expression and hyaluronan production in immortalized human granulosa cells.
authors.affiliation: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada; Center for Reproductive Medicine, The First Bethune Hospital, Jilin University, Changchun, Jilin, 130021, China.
authors.forename: Han
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada; Department of Reproductive Medicine, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Tian
authors.affiliation: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Klausen
authors.affiliation: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Center for Reproductive Medicine, The First Bethune Hospital, Jilin University, Changchun, Jilin, 130021, China. Electronic address: lrz420@126.com.
authors.forename: Ruizhi
authors.initials: R
authors.lastname: Liu
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: D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D008184:Luteal Cells / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D019485:Bone Morphogenetic Proteins; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases; D017346:Protein Serine-Threonine Kinases; D052005:Bone Morphogenetic Protein Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: BMP; HAS2; Human granulosa cell; Hyaluronan; SMAD1/5/8; SMAD2; SMAD3