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BMP-6 modulates somatostatin effects on luteinizing hormone production by gonadrotrope cells
Kishio Toma1, Fumio Otsuka2, Kohei Oguni3
1Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Abstract:
The effects of somatostatin analogs and roles of BMP-6 in the regulation of luteinizing hormone (LH) secretion were investigated using mouse gonadotrope LβT2 cells. LH mRNA expression and LH secretion induced by GnRH were suppressed by treatments with somatostatin analogs, including octreotide and pasireotide, in LβT2 cells. Of note, the inhibitory effects of somatostatin analogs on LH secretion were enhanced by the action of BMP-6. BMP-6 increased the expression levels of somatostatin receptor (SSTR)5, suggesting that BMP-6 upregulates SSTR activity that leads to reduction of GnRH-induced LH secretion. In addition, GnRH-induced phosphorylation of MAPKs including ERK, but not P38 or SAPK, was suppressed by pasireotide in the presence of BMP-6. Given that each inhibitor of ERK, JNK or P38 signaling suppressed GnRH-induced LH transcription, MAPKs are individually involved in the induction of LH production by LβT2 cells. Somatostatin analogs also impaired BMP-6-induced Smad1/5/8 phosphorylation by suppressing BMPRs and augmenting Smad6/7 expression. Collectively, the results indicate that somatostatin analogs have dual effects on the modulation of GnRH-induced MAPK signaling and BMP activity. The pituitary BMP system may play a regulatory role in GnRH-induced LH secretion by tuning the responsiveness to somatostatin analogs in gonadotrope cells.
Insights
Somatostatin analogs and BMP-6 inhibit luteinizing hormone (LH) secretion by affecting GnRH signaling in mouse cells. BMP-6 enhances somatostatin analog effects by upregulating SSTR5 and modulating MAPK and BMP signaling pathways.
Area of Science:
- Endocrinology
- Molecular Biology
- Cell Signaling
Background:
- Luteinizing hormone (LH) secretion is regulated by gonadotropin-releasing hormone (GnRH).
- Somatostatin analogs and Bone Morphogenetic Protein-6 (BMP-6) are implicated in hormonal regulation.
- Gonadotrope cells are key in LH production and release.
Purpose of the Study:
- To investigate the effects of somatostatin analogs on LH secretion.
- To elucidate the role of BMP-6 in regulating LH secretion.
- To understand the interplay between GnRH, somatostatin analogs, and BMP-6 signaling in gonadotropes.
Main Methods:
- Utilized mouse gonadotrope LβT2 cells for in vitro studies.
- Measured LH mRNA expression and LH secretion.
- Assessed the phosphorylation of MAPKs (ERK, P38, SAPK) and Smad proteins.
- Examined the expression of somatostatin receptors (SSTRs) and BMP receptors (BMPRs).
Main Results:
- Somatostatin analogs (octreotide, pasireotide) suppressed GnRH-induced LH secretion and mRNA expression.
- BMP-6 enhanced the inhibitory effects of somatostatin analogs on LH secretion.
- BMP-6 increased SSTR5 expression, suggesting enhanced somatostatin signaling.
- Pasireotide suppressed GnRH-induced ERK phosphorylation in the presence of BMP-6.
- Somatostatin analogs interfered with BMP-6-induced Smad1/5/8 phosphorylation.
Conclusions:
- Somatostatin analogs exert dual effects on GnRH-induced MAPK signaling and BMP activity.
- The pituitary BMP system modulates GnRH-induced LH secretion by influencing gonadotrope responsiveness to somatostatin analogs.
- BMP-6 plays a significant role in potentiating the inhibitory actions of somatostatin analogs on LH secretion.
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