PMID- 10999829
OWN - NLM
STAT- MEDLINE
DCOM- 20001016
LR  - 20220408
IS  - 0021-972X (Print)
IS  - 0021-972X (Linking)
VI  - 85
IP  - 9
DP  - 2000 Sep
TI  - Bone morphogenetic protein inhibits ovarian androgen production.
PG  - 3331-7
AB  - Bone morphogenetic proteins (BMPs), members of the transforming growth factor 
      beta superfamily, were recently shown to be expressed and to regulate 
      steroidogenesis in rat ovarian tissue. The purpose of this study was to 
      investigate the effect of BMP-4 on androgen production in a human ovarian 
      theca-like tumor (HOTT) cell culture model. We have previously demonstrated the 
      usefulness of these cells as a model for human thecal cells. HOTT cells respond 
      to protein kinase A agonists by increased production of androstenedione and with 
      an induction of steroid-metabolizing enzymes. In this investigation, HOTT cells 
      were treated with forskolin or dibutyryl cyclic AMP (dbcAMP) in the presence or 
      absence of various concentrations of BMP-4. The accumulation of androstenedione, 
      progesterone, and 17alpha-hydroxyprogesterone (17OHP) in the incubation medium 
      was measured by RIA. The expression of 17alpha-hydroxylase (CYP17), 
      3beta-hydroxysteroid dehydrogenase (3betaHSD), cholesterol side-chain cleavage 
      (CYP11A1), and steroidogenic acute regulatory (StAR) protein was determined by 
      protein immunoblotting analysis using specific rabbit polyclonal antibodies. We 
      also examined the expression of BMP receptor subtypes in our HOTT cells using 
      RT-PCR. In cells treated with medium alone, steroid accumulation and steroid 
      enzyme expression was unchanged. In cells treated with BMP alone there was a 
      modest decrease in androstenedione secretion. In the presence of forskolin, HOTT 
      cell production of androstenedione, 17OHP, and progesterone increased by 
      approximately 4.5-, 35-, and 3-fold, respectively. In contrast, BMP-4 decreased 
      forskolin-stimulated HOTT cell secretion of androstenedione and 17OHP by 50% but 
      increased progesterone production 3-fold above forskolin treatment alone. 
      Forskolin treatment led to an increase in CYP17, CYP11A1, 3betaHSD, and StAR 
      protein expression. BMP-4 markedly inhibited forskolin stimulation of CYP17 
      expression but had little effect on 3betaHSD, CYP11A1, or StAR protein levels. 
      Similar results were observed with the cAMP analog dbcAMP. In addition, BMP-4 
      inhibited basal and forskolin stimulation of CYP17 messenger RNA expression as 
      determined by RNase protection assay. Other members of the transforming growth 
      factor beta superfamily, including activin and inhibin, had minimal effect on 
      androstenedione production in the absence of forskolin. In the presence of 
      forskolin, activin inhibited androstenedione production by 80%. Activin also 
      inhibited forskolin induction of CYP17 protein expression as determined by 
      Western analysis. We identified the presence of messenger RNA for three BMP 
      receptors (BMP-IA, BMP-IB, and BMP-II) in the HOTT cells model. In conclusion, 
      BMP-4 inhibits HOTT cell expression of CYP17, leading to an alteration of 
      steroidogenic pathway resulting in reduced androstenedione accumulation and 
      increased progesterone production. These effects of BMP-4 seem similar to those 
      caused by activin, another member of the transforming growth factor-beta 
      superfamily of proteins.
FAU - Dooley, C A
AU  - Dooley CA
AD  - Department of Obstetrics and Gynecology, University of Texas Southwestern Medical 
      Center at Dallas, 75235-9032, USA.
FAU - Attia, G R
AU  - Attia GR
FAU - Rainey, W E
AU  - Rainey WE
FAU - Moore, D R
AU  - Moore DR
FAU - Carr, B R
AU  - Carr BR
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (Androgens)
RN  - 0 (BMP4 protein, human)
RN  - 0 (Bmp4 protein, rat)
RN  - 0 (Bone Morphogenetic Protein 4)
RN  - 0 (Bone Morphogenetic Proteins)
RN  - 0 (Proteins)
RN  - 0 (Steroids)
RN  - 57285-09-3 (Inhibins)
RN  - 63231-63-0 (RNA)
RN  - EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase)
RN  - EC 3.1.- (Ribonucleases)
SB  - IM
MH  - Androgens/*biosynthesis
MH  - Blotting, Western
MH  - Bone Morphogenetic Protein 4
MH  - Bone Morphogenetic Proteins/*pharmacology
MH  - Cell Separation
MH  - Female
MH  - Humans
MH  - Inhibins/pharmacology
MH  - Ovarian Neoplasms/enzymology/metabolism
MH  - Ovary/drug effects/*metabolism
MH  - Proteins/chemistry
MH  - RNA/analysis/isolation & purification
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Ribonucleases/antagonists & inhibitors
MH  - Steroid 17-alpha-Hydroxylase/biosynthesis
MH  - Steroids/analysis/biosynthesis
MH  - Theca Cells/enzymology/metabolism
MH  - Thecoma/enzymology/metabolism
MH  - Tumor Cells, Cultured
EDAT- 2000/09/22 11:00
MHDA- 2000/10/21 11:01
CRDT- 2000/09/22 11:00
PHST- 2000/09/22 11:00 [pubmed]
PHST- 2000/10/21 11:01 [medline]
PHST- 2000/09/22 11:00 [entrez]
AID - 10.1210/jcem.85.9.6835 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 2000 Sep;85(9):3331-7. doi: 10.1210/jcem.85.9.6835.