title: Bone Morphogenetic Protein-4 (BMP4): A Paracrine Regulator of Human Adrenal C19 Steroid Synthesis.
abstract: Bone morphogenetic proteins (BMPs) comprise one of the largest subgroups in the TGF-β ligand superfamily. We have identified a functional BMP system equipped with the ligand (BMP4), receptors (BMP type II receptor, BMP type IA receptor, also called ALK3) and the signaling proteins, namely the mothers against decapentaplegic homologs 1, 4, and 5 in the human adrenal gland and the human adrenocortical cell line H295R. Microarray, quantitative RT-PCR, and immunohistochemistry confirmed that BMP4 expression was highest in the adrenal zona glomerulosa followed by the zona fasciculata and zona reticularis. Treatment of H295R cells with BMP4 caused phosphorylation of the mothers against decapentaplegic and a profound decrease in synthesis of the C19 steroids dehydroepiandrosterone (DHEA), DHEA sulfate, and androstenedione. Administration of BMP4 to cultures of H295R cells also caused a profound decrease in the mRNA and protein levels of 17α-hydroxylase/17,20-lyase (CYP17A1 and P450c17, respectively) but no significant effect on the mRNA levels of cholesterol side-chain cleavage cytochrome P450 (CYP11A1) or type 2 3β-hydroxysteroid dehydrogenase (HSD3B2). Furthermore, Noggin (a BMP inhibitor) was able to reverse the negative effects of BMP4 with respect to both CYP17A1 transcription and DHEA secretion in the H295R cell line. Collectively the present data suggest that BMP4 is an autocrine/paracrine negative regulator of C19 steroid synthesis in the human adrenal and works by suppressing P450c17.
authors: Department of Molecular and Integrative Physiology (J.R., H.K.N., K.N., W.E.R.), and Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan (R.J.A.), Ann Arbor, Michigan 48109-5622; and School of Pediatrics and Reproductive Health (R.J.R.), Robinson Research Institute, University of Adelaide, South Australia 5005, Australia.
authors: Juilee
authors: J
authors: Rege
authors: Department of Molecular and Integrative Physiology (J.R., H.K.N., K.N., W.E.R.), and Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan (R.J.A.), Ann Arbor, Michigan 48109-5622; and School of Pediatrics and Reproductive Health (R.J.R.), Robinson Research Institute, University of Adelaide, South Australia 5005, Australia.
authors: Hiromi Koso
authors: HK
authors: Nishimoto
authors: Department of Molecular and Integrative Physiology (J.R., H.K.N., K.N., W.E.R.), and Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan (R.J.A.), Ann Arbor, Michigan 48109-5622; and School of Pediatrics and Reproductive Health (R.J.R.), Robinson Research Institute, University of Adelaide, South Australia 5005, Australia.
authors: Koshiro
authors: K
authors: Nishimoto
authors: Department of Molecular and Integrative Physiology (J.R., H.K.N., K.N., W.E.R.), and Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan (R.J.A.), Ann Arbor, Michigan 48109-5622; and School of Pediatrics and Reproductive Health (R.J.R.), Robinson Research Institute, University of Adelaide, South Australia 5005, Australia.
authors: Raymond J
authors: RJ
authors: Rodgers
authors: Department of Molecular and Integrative Physiology (J.R., H.K.N., K.N., W.E.R.), and Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan (R.J.A.), Ann Arbor, Michigan 48109-5622; and School of Pediatrics and Reproductive Health (R.J.R.), Robinson Research Institute, University of Adelaide, South Australia 5005, Australia.
authors: Richard J
authors: RJ
authors: Auchus
authors: Department of Molecular and Integrative Physiology (J.R., H.K.N., K.N., W.E.R.), and Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan (R.J.A.), Ann Arbor, Michigan 48109-5622; and School of Pediatrics and Reproductive Health (R.J.R.), Robinson Research Institute, University of Adelaide, South Australia 5005, Australia.
authors: William E
authors: WE
authors: Rainey
mesh_terms: D000302:Adrenal Cortex / Q000378:metabolism*; D000311:Adrenal Glands / Q000378:metabolism; D000735:Androstenedione / Q000096:biosynthesis*; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D002460:Cell Line; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000187:drug effects / Q000235:genetics; D003687:Dehydroepiandrosterone / Q000096:biosynthesis*; D019314:Dehydroepiandrosterone Sulfate / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D019899:Paracrine Communication / Q000235:genetics; D011375:Progesterone Reductase / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051898:Smad1 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000187:drug effects / Q000235:genetics; D015383:Zona Fasciculata / Q000378:metabolism; D015384:Zona Glomerulosa / Q000378:metabolism; D015385:Zona Reticularis / Q000378:metabolism
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D012333:RNA, Messenger; C497399:SMAD1 protein, human; C497796:SMAD4 protein, human; C497797:SMAD5 protein, human; D051898:Smad1 Protein; D051901:Smad4 Protein; D051902:Smad5 Protein; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; C533068:3 beta-hydroxysteroid dehydrogenase type II; D011375:Progesterone Reductase; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II