ArticleProceedings of the National Academy of Sciences of the United States of America2013
Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers, 1 of them a synthesis that pooled it.
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Who cites it
38 citing papers in PubMed, 1 synthesis or guideline pooled it, 75 citations in OpenAlex.
- Identification of risk loci for primary aldosteronism in genome-wide association studies.Nature communications · 2022Pooled it
- New Insights into the Mechanism of Insulin-like Peptide 3 (International journal of molecular sciences · 2025Article
- Decoding androgen excess in polycystic ovary syndrome: Roles of insulin resistance and other key intraovarian and systemic factors.World journal of diabetes · 2025Review
- Potential ability of circulating INSL3 level for the prediction of ovarian reserve and IVF success as a novel theca cell-specific biomarker in women with unexplained infertility and diminished ovarian reserve.Reproductive biology and endocrinology : RB&E · 2025Article
- PCOS and Inositols - Advances and Lessons We are Learning. A Narrative Review.Drug design, development and therapy · 2025Review
- Discovery of RXFP2 genetic association in resistant hypertensive men and RXFP2 antagonists for the treatment of resistant hypertension.Scientific reports · 2024Article
- Targeted deletion of NR2F2 and VCAM1 in theca cells impacts ovarian follicular development: insights into polycystic ovary syndrome?†.Biology of reproduction · 2024Article
- Serum INSL3 measured by LC-MS/MS in pubertal girls and in girls with precocious puberty during GnRH agonist treatment.Frontiers in endocrinology · 2024Article
- Does kisspeptin exert a local modulatory effect on bovine ovarian steroidogenesis?Reproduction & fertility · 2023Article
- Quantitative analyses of insulin-like peptide 3 and sex steroid hormones in dominant follicles and corpora lutea during the estrus cycle and in follicular cysts in beef heifers.The Journal of reproduction and development · 2022Article
- Mesenchymal Stem Cell-Conditioned Media Regulate Steroidogenesis and Inhibit Androgen Secretion in a PCOS Cell Model via BMP-2.International journal of molecular sciences · 2021Article
- Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals.Archives of toxicology · 2020Review
- Diverse functions of insulin-like 3 peptide.The Journal of endocrinology · 2020Review
- Identifying genes associated with the development of human polycystic ovary syndrome.Saudi journal of biological sciences · 2020Review
- 'Free' inhibin α subunit is expressed by bovine ovarian theca cells and its knockdown suppresses androgen production.Scientific reports · 2019Article
- Temperature and insulin signaling regulate body size in Hydra by the Wnt and TGF-beta pathways.Nature communications · 2019Article
- Transcript abundance of stromal and thecal cell related genes during bovine ovarian development.PloS one · 2019Article
- Ovarian Follicular Theca Cell Recruitment, Differentiation, and Impact on Fertility: 2017 Update.Endocrine reviews · 2018Review
- Genetic Variants Associated with Hyperandrogenemia in PCOS Pathophysiology.Genetics research international · 2018Review
- Sex steroid production associated with puberty is absent in germ cell-free salmon.Scientific reports · 2017Article
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 3 countries.
Funding
Abstract
Bone morphogenetic proteins (BMPs) are firmly implicated as intra-ovarian regulators of follicle development and steroidogenesis. Here we report a microarray analysis showing that treatment of cultured bovine theca cells (TC) with BMP6 significantly (>twofold; P < 0.01) up- or down-regulated expression of 445 genes. Insulin-like peptide 3 (INSL3) was the most heavily down-regulated gene (-43-fold) with cytochrome P450, subfamily XVII (CYP17A1) and other key steroidogenic transcripts including steroidogenic acute regulatory protein (STAR), cytochrome P450 family 11, subfamily A1 (CYP11A1) and 3 beta-hydroxysteroid dehydrogenase type 1 (HSD3B1) also down-regulated. BMP6 also reduced expression of nuclear receptor subfamily 5A1 (NR5A1) known to target the promoter regions of the aforementioned genes. Real-time PCR confirmed these findings and also revealed a marked reduction in expression of INSL3 receptor, relaxin/insulin-like family peptide receptor 2 (RXFP2). Secretion of INSL3 protein and androstenedione were also suppressed suggesting a functional link between BMP and INSL3 pathways in controlling androgen synthesis. RNAi-mediated knockdown of INSL3 reduced INSL3 mRNA (75%) and protein (94%) level and elicited a 77% reduction in CYP17A1 mRNA and 83% reduction in androstenedione secretion. Knockdown of RXFP2 also reduced CYP17A1 expression (81%) and androstenedione secretion (88%). Conversely, treatment with exogenous (human) INSL3 increased androstenedione secretion ∼twofold. The CYP17A1 inhibitor abiraterone abolished androgen secretion and reduced expression of both INSL3 and RXFP2. Collectively, these findings indicate a positive autoregulatory role for INSL3 signaling in maintaining thecal androgen production, and visa versa. Moreover, BMP6-induced suppression of thecal androgen synthesis may be mediated, at least in part, by reduced INSL3-RXFP2 signaling.
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