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Growth Differentiation Factor-8 Decreases StAR Expression Through ALK5-Mediated Smad3 and ERK1/2 Signaling Pathways
Lanlan Fang1, Hsun-Ming Chang1, Jung-Chien Cheng1
1Reproductive Medical Center (L.F., Y.Y., Y.-P.S.), The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China 450052; and Department of Obstetrics and Gynaecology (H.-M.C., J.-C.C., P.C.K.L.), Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
Abstract:
Growth differentiation factor-8 (GDF-8) has been recently shown to be expressed in human granulosa cells, and the mature form of GDF-8 protein can be detected in the follicular fluid. However, the biological function and significance of this growth factor in the human ovary remains to be determined. Here, we investigated the effects of GDF-8 on steroidogenic enzyme expression and the potential mechanisms of action in luteinized human granulosa cells. We demonstrated that treatment with GDF-8 did not affect the mRNA levels of P450 side-chain cleavage enzyme and 3β-hydroxysteroid dehydrogenase, whereas it significantly down-regulated steroidogenic acute regulatory protein (StAR) expression and decreased progesterone production. The suppressive effect of GDF-8 on StAR expression was abolished by the inhibition of the TGF-β type I receptor. In addition, treatment with GDF-8 activated both Smad2/3 and ERK1/2 signaling pathways. Furthermore, knockdown of activin receptor-like kinase 5 reversed the effects of GDF-8 on Smad2/3 phosphorylation and StAR expression. The inhibition of Smad3 or ERK1/2 signaling pathways attenuated the GDF-8-induced down-regulation of StAR and production of progesterone. Interestingly, the concentrations of GDF-8 were negatively correlated with those of progesterone in human follicular fluid. These results indicate a novel autocrine function of GDF-8 to down-regulate StAR expression and decrease progesterone production in luteinized human granulosa cells, most likely through activin receptor-like kinase 5-mediated Smad3 and ERK1/2 signaling pathways. Our findings suggest that granulosa cells might play a critical role in the regulation of progesterone production to prevent premature luteinization during the final stage of folliculogenesis.
Insights
Growth differentiation factor-8 (GDF-8) inhibits progesterone production in human granulosa cells by down-regulating steroidogenic acute regulatory protein (StAR) expression via Smad3 and ERK1/2 pathways.
Area of Science:
- Reproductive Biology
- Endocrinology
- Cell Signaling
Background:
- Growth differentiation factor-8 (GDF-8) is expressed in human granulosa cells, with its mature protein found in follicular fluid.
- The precise biological role of GDF-8 within the human ovary remains largely undetermined.
- Understanding GDF-8's function is crucial for elucidating ovarian regulation mechanisms.
Purpose of the Study:
- To investigate the effects of GDF-8 on steroidogenic enzyme expression in luteinized human granulosa cells.
- To explore the underlying molecular mechanisms through which GDF-8 exerts its actions.
- To determine the significance of GDF-8 in regulating progesterone production.
Main Methods:
- Luteinized human granulosa cells were treated with GDF-8.
- mRNA levels of steroidogenic enzymes, including StAR, were quantified.
- Signaling pathways (Smad2/3, ERK1/2) and receptor involvement (TGF-β type I receptor, ALK5) were analyzed using inhibition and knockdown techniques.
- Progesterone production was measured.
Main Results:
- GDF-8 significantly down-regulated steroidogenic acute regulatory protein (StAR) expression and decreased progesterone production.
- GDF-8's suppressive effect on StAR was mediated through the TGF-β type I receptor.
- GDF-8 activated both Smad2/3 and ERK1/2 signaling pathways.
- Knockdown of activin receptor-like kinase 5 (ALK5) reversed GDF-8's effects on Smad2/3 and StAR.
- Inhibition of Smad3 or ERK1/2 pathways attenuated GDF-8's impact on StAR and progesterone.
- GDF-8 concentrations negatively correlated with progesterone levels in human follicular fluid.
Conclusions:
- GDF-8 exhibits a novel autocrine function to decrease StAR expression and progesterone production in luteinized human granulosa cells.
- This regulation is primarily mediated via activin receptor-like kinase 5 (ALK5)-dependent Smad3 and ERK1/2 signaling pathways.
- Granulosa cells may play a key role in controlling progesterone production to prevent premature luteinization during folliculogenesis.
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