G Protein-Coupled Estrogen Receptor Mediates Cell Proliferation through the cAMP/PKA/CREB Pathway in Murine Bone Marrow Mesenchymal Stem Cells

Estrogen is an important hormone to regulate skeletal physiology via estrogen receptors. The traditional estrogen receptors are ascribed to two nuclear estrogen receptors (ERs), ERα and ERβ. Moreover, G protein-coupled estrogen receptor-1 (GPER-1) was reported as a membrane receptor for estrogen in...

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Published in:	International journal of molecular sciences 2020-09, Vol.21 (18), p.6490
Main Authors:	Chuang, Shu-Chun, Chen, Chung-Hwan, Chou, Ya-Shuan, Ho, Mei-Ling, Chang, Je-Ken
Format:	Article
Language:	eng
Subjects:	Animals Biomedical materials BMSCs Bone marrow Bone Marrow Cells - metabolism Cell cycle Cell division Cell growth Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Cell viability Chondrocytes Cyclic AMP - metabolism Cyclic AMP response element-binding protein Cyclic AMP Response Element-Binding Protein - metabolism Cyclic AMP-Dependent Protein Kinases - metabolism Cyclin D1 Cyclin-dependent kinase 2 Estradiol - pharmacology estrogen estrogen receptor Estrogen Receptor alpha - metabolism Estrogen receptors Estrogens Estrogens - metabolism Estrogens - pharmacology Female Gene expression GPER-1 Growth plate Kinases Male Mesenchymal stem cells Mesenchymal Stem Cells - metabolism Mice Neonates Osteoblasts Osteocytes Phosphorylation Protein kinase A Proteins Puberty Rats Rats, Sprague-Dawley Receptors, Estrogen - metabolism Receptors, Estrogen - physiology Receptors, G-Protein-Coupled - metabolism Receptors, G-Protein-Coupled - physiology Regulators Sexual Maturation - drug effects Signal transduction Signal Transduction - drug effects Signaling siRNA Stem cell transplantation Stem cells Transcriptional Activation - drug effects
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Summary:	Estrogen is an important hormone to regulate skeletal physiology via estrogen receptors. The traditional estrogen receptors are ascribed to two nuclear estrogen receptors (ERs), ERα and ERβ. Moreover, G protein-coupled estrogen receptor-1 (GPER-1) was reported as a membrane receptor for estrogen in recent years. However, whether GPER-1 regulated osteogenic cell biology on skeletal system is still unclear. GPER-1 is expressed in growth plate abundantly before puberty but decreased abruptly since the very late stage of puberty in humans. It indicates GPER-1 might play an important role in skeletal growth regulation. GPER-1 expression has been confirmed in osteoblasts, osteocytes and chondrocytes, but its expression in mesenchymal stem cells (MSCs) has not been confirmed. In this study, we hypothesized that GPER-1 is expressed in bone MSCs (BMSC) and enhances BMSC proliferation. The cultured tibiae of neonatal rat and murine BMSCs were tested in our study. GPER-1-specific agonist (G-1) and antagonist (G-15), and GPER-1 siRNA (siGPER-1) were used to evaluate the downstream signaling pathway and cell proliferation. Our results revealed BrdU-positive cell counts were higher in cultured tibiae in the G-1 group. The G-1 also enhanced the cell viability and proliferation, whereas G-15 and siGPER-1 reduced these activities. The cAMP and phosphorylation of CREB were enhanced by G-1 but inhibited by G-15. We further demonstrated that GPER-1 mediates BMSC proliferation via the cAMP/PKA/p-CREB pathway and subsequently upregulates cell cycle regulators, cyclin D1/cyclin-dependent kinase (CDK) 6 and cyclin E1/CDK2 complex. The present study is the first to report that GPER-1 mediates BMSC proliferation. This finding indicates that GPER-1 mediated signaling positively regulates BMSC proliferation and may provide novel insights into addressing estrogen-mediated bone development.
ISSN:	1422-0067 1661-6596 1422-0067