Ghrelin Increases Beta-Catenin Level through Protein Kinase A Activation and Regulates OPG Expression in Rat Primary Osteoblasts
Ghrelin, by binding growth hormone secretagogue receptor (GHS-R), promotes osteoblast proliferation but the signaling mechanism of GHS-R on these cells remains unclear. Since canonical Wnt/β-catenin pathway is critically associated with bone homeostasis, we investigated its involvement in mediating...
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| Format: | Article |
| Language: | English |
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Wiley
2015-01-01
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| Series: | International Journal of Endocrinology |
| Online Access: | http://dx.doi.org/10.1155/2015/547473 |
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| author | Emanuela Mrak Lavinia Casati Francesca Pagani Alessandro Rubinacci Guido Zarattini Valeria Sibilia |
| author_facet | Emanuela Mrak Lavinia Casati Francesca Pagani Alessandro Rubinacci Guido Zarattini Valeria Sibilia |
| author_sort | Emanuela Mrak |
| collection | DOAJ |
| description | Ghrelin, by binding growth hormone secretagogue receptor (GHS-R), promotes osteoblast proliferation but the signaling mechanism of GHS-R on these cells remains unclear. Since canonical Wnt/β-catenin pathway is critically associated with bone homeostasis, we investigated its involvement in mediating ghrelin effects in osteoblasts and in osteoblast-osteoclast cross talk. Ghrelin (10−10M) significantly increased β-catenin levels in rat osteoblasts (rOB). This stimulatory action on β-catenin involves a specific interaction with GHS-R1a, as it is prevented by the selective GHS-R1a antagonist, D-Lys3-GHRP-6 (10−7M). The effect of ghrelin on β-catenin involves the phosphorylation and inactivation of GSK-3β via protein kinase A (PKA). Inhibition of PKA activity reduces the facilitatory action of ghrelin on β-catenin stabilization. Ghrelin treatment of rOB significantly increases the expression of osteoprotegerin (OPG), which plays an important role in the regulation of osteoclastogenesis, and this effect is blocked by D-Lys3-GHRP-6. Furthermore, ghrelin reduced RANKL/OPG ratio thus contrasting osteoclastogenesis. Accordingly, conditioned media from rOB treated with ghrelin decreased the number of multinucleated TRAcP+ cells as compared with the conditioned media from untreated-control rOB. Our data suggest new roles for ghrelin in modulating bone homeostasis via a specific interaction with GHSR-1a in osteoblasts with subsequent enhancement of both β-catenin levels and OPG expression. |
| format | Article |
| id | doaj-art-f104774447024680894976de246acdea |
| institution | Kabale University |
| issn | 1687-8337 1687-8345 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | International Journal of Endocrinology |
| spelling | doaj-art-f104774447024680894976de246acdea2025-02-03T05:47:17ZengWileyInternational Journal of Endocrinology1687-83371687-83452015-01-01201510.1155/2015/547473547473Ghrelin Increases Beta-Catenin Level through Protein Kinase A Activation and Regulates OPG Expression in Rat Primary OsteoblastsEmanuela Mrak0Lavinia Casati1Francesca Pagani2Alessandro Rubinacci3Guido Zarattini4Valeria Sibilia5Department of Medical Biotechnology and Translational Medicine, Medical Pharmacology Unit, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano, ItalyDepartment of Medical Biotechnology and Translational Medicine, Medical Pharmacology Unit, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano, ItalyDepartment of Medical Biotechnology and Translational Medicine, Medical Pharmacology Unit, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano, ItalyBone Metabolism Unit, Scientific Institute San Raffaele, Via Olgettina 60, 20132 Milano, ItalyDepartment of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Viale Europa 11, 25123 Brescia, ItalyDepartment of Medical Biotechnology and Translational Medicine, Medical Pharmacology Unit, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano, ItalyGhrelin, by binding growth hormone secretagogue receptor (GHS-R), promotes osteoblast proliferation but the signaling mechanism of GHS-R on these cells remains unclear. Since canonical Wnt/β-catenin pathway is critically associated with bone homeostasis, we investigated its involvement in mediating ghrelin effects in osteoblasts and in osteoblast-osteoclast cross talk. Ghrelin (10−10M) significantly increased β-catenin levels in rat osteoblasts (rOB). This stimulatory action on β-catenin involves a specific interaction with GHS-R1a, as it is prevented by the selective GHS-R1a antagonist, D-Lys3-GHRP-6 (10−7M). The effect of ghrelin on β-catenin involves the phosphorylation and inactivation of GSK-3β via protein kinase A (PKA). Inhibition of PKA activity reduces the facilitatory action of ghrelin on β-catenin stabilization. Ghrelin treatment of rOB significantly increases the expression of osteoprotegerin (OPG), which plays an important role in the regulation of osteoclastogenesis, and this effect is blocked by D-Lys3-GHRP-6. Furthermore, ghrelin reduced RANKL/OPG ratio thus contrasting osteoclastogenesis. Accordingly, conditioned media from rOB treated with ghrelin decreased the number of multinucleated TRAcP+ cells as compared with the conditioned media from untreated-control rOB. Our data suggest new roles for ghrelin in modulating bone homeostasis via a specific interaction with GHSR-1a in osteoblasts with subsequent enhancement of both β-catenin levels and OPG expression.http://dx.doi.org/10.1155/2015/547473 |
| spellingShingle | Emanuela Mrak Lavinia Casati Francesca Pagani Alessandro Rubinacci Guido Zarattini Valeria Sibilia Ghrelin Increases Beta-Catenin Level through Protein Kinase A Activation and Regulates OPG Expression in Rat Primary Osteoblasts International Journal of Endocrinology |
| title | Ghrelin Increases Beta-Catenin Level through Protein Kinase A Activation and Regulates OPG Expression in Rat Primary Osteoblasts |
| title_full | Ghrelin Increases Beta-Catenin Level through Protein Kinase A Activation and Regulates OPG Expression in Rat Primary Osteoblasts |
| title_fullStr | Ghrelin Increases Beta-Catenin Level through Protein Kinase A Activation and Regulates OPG Expression in Rat Primary Osteoblasts |
| title_full_unstemmed | Ghrelin Increases Beta-Catenin Level through Protein Kinase A Activation and Regulates OPG Expression in Rat Primary Osteoblasts |
| title_short | Ghrelin Increases Beta-Catenin Level through Protein Kinase A Activation and Regulates OPG Expression in Rat Primary Osteoblasts |
| title_sort | ghrelin increases beta catenin level through protein kinase a activation and regulates opg expression in rat primary osteoblasts |
| url | http://dx.doi.org/10.1155/2015/547473 |
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