Molecular Basis of Bone Morphogenetic Protein-15 Signaling in Granulosa Cells

Moore, R. Kelly; Otsuka, Fumio; Shimasaki, Shunichi

doi:10.1074/jbc.m207362200

Cited by 288 publications

(248 citation statements)

References 51 publications

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“…Moreover, the ERK1/ERK2 and SAPK/JNK pathways are linked to TGF-b/BMP signal transduction in some cell types. [46][47][48] The data provided here show that the MAPK pathway is functionally involved in PAH-PASMC mitosis, which is facilitated under the presence of combined stimuli of either ET1 or aldosterone and the BMP system. Effects of BMP on endothelin-and aldosterone-induced MAPK activation in PASMCs.…”

Section: Discussionmentioning

confidence: 89%

Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

et al. 2010

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Recent genetic studies have uncovered a link between familial and idiopathic pulmonary arterial hypertension (PAH) and germline mutations in the bone morphogenetic protein type-II receptor (BMPRII). The pathology of PAH is characterized by remodeling of the pulmonary arteries due to pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Although increased endothelial injury and impaired suppression of PASMC proliferation are both critical for the cellular pathogenesis of PAH, a detailed molecular mechanism underlying PAH has yet to be elucidated. In the present study, we investigated the roles of the BMP system and other vasoactive factors associated with PAH (including endothelin (ET), angiotensin II (Ang II) and aldosterone) in the mitotic actions of PASMCs isolated from idiopathic and secondary PAH lungs. ET1 and aldosterone stimulated PASMC proliferation of idiopathic PAH more effectively than secondary PAH, whereas Ang II and ET3 failed to activate mitosis in either of the PASMC cell type. The effects of ET1 and aldosterone were blocked by bosentan, an ET type-A/B receptor (ETA/BR) antagonist, and eplerenone, a selective mineralocorticoid receptor (MR) blocker, respectively. Among the BMP ligands examined, BMP-2 and BMP-7, but not BMP-4 or BMP-6, significantly increased cell mitosis in both PASMC cell types. Notably, ET1-and aldosterone-induced mitosis and mitogen-activated protein kinase phosphorylation were significantly increased in the presence of BMP-2 and BMP-7 in PASMCs isolated from idiopathic PAH, although additive effects were not observed in PASMCs isolated from secondary PAH. Inhibition of extracellular signal-regulated kinase 1 (ERK1)/ERK2 signaling suppressed basal-, ET1-and aldosterone-induced PASMC mitosis more potently than that of stress-activated protein kinase/c-Jun NH2-terminal kinase inhibition. Given the fact that BMP-2 and BMP-7 upregulated ETA/BR and MR expression and that BMP-2 decreased 11bHSD2 (11b-hydroxysteroid dehydrogenase type 2) levels in PASMCs isolated from idiopathic PAH, BMPR-Smad signaling may have a key role in amplifying the ETA/BR and/or MR-ERK signaling in PASMCs of the PAH lung. Collectively, the functional link between BMP and ET and/or the MR system may be involved in the progress of PASMC mitosis, ultimately leading to the development of clinical PAH.

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Section: Discussionmentioning

confidence: 89%

Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

et al. 2010

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“…Similarly, BMP15 inhibits the production of progesterone induced by 8-bromo-AMPc in follicular cells [45]. BMP15 has been shown to activate the Smad 1/5/8 pathway through BMPR2 and ALK6 [29], with BMPR2 having the greatest effect on BMP15 suppression of FSH-induced progesterone production [28]. Moreover, a recent study reports the co-operative effects of GDF9 and BMP15, modulated through BMPR2, on inhibition of FSH-stimulated progesterone production [28] that reinforces our results.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the BMPR2 has been identified as the receptor that primarily modulates the cooperative effects of GDF9 and BMP15 on rat granulosa cells function, with BMPR2 having the greatest effect on BMP15 suppression of FSHinduced progesterone production [28]. Furthermore, the type 2 receptor is appointed as the most effective in BMP15 bioactivity [29].…”

Section: Introductionmentioning

confidence: 99%

Single-cell expression analysis of BMP15 and GDF9 in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation

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Vireque

Santana

et al. 2012

J Assist Reprod Genet

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Purpose To detect expression of bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) in oocytes, and their receptor type 2 receptor for BMPs (BMPR2) in cumulus cells in women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF), and determine if BMPR2, BMP15, and GDF9 expression correlate with hyperandrogenism in FF of PCOS patients. Methods Prospective case-control study. Eighteen MIIoocytes and their respective cumulus cells were obtained from 18 patients with PCOS, and 48 MII-oocytes and cumulus cells (CCs) from 35 controls, both subjected to controlled ovarian hyperstimulation (COH), and follicular fluid (FF) was collected from small (10-14 mm) and large (>18 mm) follicles. RNeasy Micro Kit (Qiagen ® ) was used for RNA extraction and gene expression was quantified in each oocyte individually and in microdissected cumulus cells from cumulus-oocyte complexes retrieved from preovulatory follicles using qRT-PCR. Chemiluminescence and RIA assays were used for hormone assays. Results BMP15 and GDF9 expression per oocyte was higher among women with PCOS than the control group. A positive correlation was found between BMPR2 transcripts and hyperandrogenism in FF of PCOS patients. Progesterone values in FF were lower in the PCOS group. Conclusion We inferred that BMP15 and GDF9 transcript levels increase in mature PCOS oocytes after COH, and might inhibit the progesterone secretion by follicular cells in PCOS follicles, preventing premature luteinization in cumulus cells. BMPR2 expression in PCOS cumulus cells might be regulated by androgens.

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“…However, a low level of ALK6 protein has been detected in theca by immunohistochemistry suggesting that this receptor might be present [29]. In rats, BMP15 binds to ALK6 with very little affinity for ALK3 and BMPR-II inhibits BMP15 induced cell functions [22] suggesting that cells expressing both ALK6 and BMPR-II are probable targets for the BMP15 ligand. If this holds true for sheep, then it is likely that granulosa cells and the oocyte are affected by oocyte-derived BMP15 from the type 2 stage of growth [33].…”

Section: Intraovarian Sites Of Bmp15 and Gdf9 Gene Expression And Posmentioning

confidence: 99%

Physiological effects of major genes affecting ovulation rate in sheep

et al. 2005

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-Genetic mutations with major effects on ovulation rate in sheep were recently identified in two genes of the transforming growth factor (TGFβ) superfamily and a TGFβ receptor, namely bone morphogenetic protein 15 (BMP15), otherwise known as the growth differentiation factor 9b (GDF9b), GDF9 and activin-like kinase 6 (ALK6) otherwise known as the BMP receptor type IB (BMPRIB). Animals homozygous for the BMP15 or GDF9 mutations are anovulatory whereas animals heterozygous for BMP15 or GDF9 or heterozygous or homozygous for ALK6 have higher than normal ovulation rates. Immunisation of ewes against BMP15 or GDF9 shows that both are essential for normal follicular development and control of ovulation rate. Common features of fertile animals with the BMP15, ALK6 (and possibly GDF9) mutations are changes in oocyte development during early preantral follicular growth, earlier maturation of granulosa cells and ovulation of mature follicles at smaller diameters. In summary, these findings have led to a new paradigm in reproductive biology, namely that the oocyte plays a key role in regulating the ovulation rate. genetic mutations / BMP15 / GDF9 / ALK6 / BMPR-IB

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Molecular Basis of Bone Morphogenetic Protein-15 Signaling in Granulosa Cells

Cited by 288 publications

References 51 publications

Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

Single-cell expression analysis of BMP15 and GDF9 in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation

Physiological effects of major genes affecting ovulation rate in sheep

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