title: BMP15 suppresses progesterone production by down-regulating StAR via ALK3 in human granulosa cells.
abstract: In addition to somatic cell-derived growth factors, oocyte-derived growth differentiation factor (GDF)9 and bone morphogenetic protein (BMP)15 play essential roles in female fertility. However, few studies have investigated their effects on human ovarian steroidogenesis, and fewer still have examined their differential effects or underlying molecular determinants. In the present study, we used immortalized human granulosa cells (SVOG) and human granulosa cell tumor cells (KGN) to compare the effects of GDF9 and BMP15 on steroidogenic enzyme expression and investigate potential mechanisms of action. In SVOG cells, neither GDF9 nor BMP15 affects the mRNA levels of P450 side-chain cleavage enzyme or 3β-hydroxysteroid dehydrogenase. However, treatment with BMP15, but not GDF9, significantly decreases steroidogenic acute regulatory protein (StAR) mRNA and protein levels as well as progesterone production. These suppressive effects, along with the induction of Sma and Mad-related protein (SMAD)1/5/8 phosphorylation, are attenuated by cotreatment with 2 different BMP type I receptor inhibitors (dorsomorphin and DMH-1). Furthermore, depletion of activin receptor-like kinase (ALK)3 using small interfering RNA reverses the effects of BMP15 on SMAD1/5/8 phosphorylation and StAR expression. Similarly, knockdown of ALK3 abolishes BMP15-induced SMAD1/5/8 phosphorylation in KGN cells. These results provide evidence that oocyte-derived BMP15 down-regulates StAR expression and decreases progesterone production in human granulosa cells, likely via ALK3-mediated SMAD1/5/8 signaling. Our findings suggest that oocyte may play a critical role in the regulation of progesterone to prevent premature luteinization during the late stage of follicle development.
authors.affiliation: PhD, FCAHS, FRSC, Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Room 317, 950 West 28th Avenue, Vancouver, British Columbia, Canada, V5Z 4H4. peter.leung@ubc.ca.
authors.forename: Hsun-Ming
authors.initials: HM
authors.lastname: Chang
authors.forename: Jung-Chien
authors.initials: JC
authors.lastname: Cheng
authors.forename: Christian
authors.initials: C
authors.lastname: Klausen
authors.forename: Peter C K
authors.initials: PC
authors.lastname: Leung
mesh_terms: D055430:Bone Morphogenetic Protein 15 / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D055429:Growth Differentiation Factor 9 / Q000494:pharmacology; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011374:Progesterone / Q000096:biosynthesis*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D055430:Bone Morphogenetic Protein 15; C583032:DMH1 compound; C525897:GDF9 protein, human; D055429:Growth Differentiation Factor 9; D010750:Phosphoproteins; D011720:Pyrazoles; D011743:Pyrimidines; D011804:Quinolines; D012333:RNA, Messenger; D051785:Smad Proteins; D000098682:Steroidogenic Acute Regulatory Protein; C516138:dorsomorphin; D011374:Progesterone; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I