FXR Activation Accelerates Early Phase of Osteoblast Differentiation Through COX-2-PGE<sub>2</sub>-EP4 Axis in BMP-2-Induced Mouse Mesenchymal Stem Cells
Farnesoid X receptor (FXR), a nuclear receptor, is expressed in calvaria and bone marrow stromal cells and plays a role in bone homeostasis. However, the mechanism of FXR-activated osteoblast differentiation remains unclear. In this study, we investigated the regulatory mechanism underlying FXR-acti...
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2024-12-01
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| author | Ko Fujimori Yusuke Iguchi Yukiko Yamashita Keigo Gohda Naoki Teno |
| author_facet | Ko Fujimori Yusuke Iguchi Yukiko Yamashita Keigo Gohda Naoki Teno |
| author_sort | Ko Fujimori |
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| description | Farnesoid X receptor (FXR), a nuclear receptor, is expressed in calvaria and bone marrow stromal cells and plays a role in bone homeostasis. However, the mechanism of FXR-activated osteoblast differentiation remains unclear. In this study, we investigated the regulatory mechanism underlying FXR-activated osteoblast differentiation using bone morphogenetic protein-2 (BMP-2)-induced mouse ST-2 mesenchymal stem cells. We also synthesized a novel FXR agonist, <b>FLG390</b>, and compared its biological effects in osteoblast differentiation with a known FXR agonist, chenodeoxycholic acid (CDCA). As an FXR agonist, <b>FLG390</b> accelerated osteoblast differentiation to a comparable extent with CDCA, enhancing alkaline phosphatase (ALP) activity and the expression of osteoblast differentiated-related genes such as ALP, collagen type 1 α1 chain (COL1A1), and runt-related transcription factor 2 (RUNX2). FXR activation elevated the expression of cyclooxygenase (COX)-2 and the production of prostaglandin (PG) E<sub>2</sub> in the early phase of osteoblast differentiation. A selective COX-2 inhibitor and an antagonist of EP4 receptors, one of PGE<sub>2</sub> receptors, partially suppressed FXR-activated osteoblast differentiation. Moreover, treatment with either inhibitor during the first 6 h after initiating osteoblast differentiation repressed FXR-activated osteoblast differentiation to the same extent as did the treatment for 6 d. Therefore, a novel FXR agonist, <b>FLG390,</b> exhibited potency comparable to CDCA. FXR activation promoted the early phase of osteoblast differentiation via the COX-2-PGE<sub>2</sub>-EP4 axis, representing a potential target for control of bone metabolism. |
| format | Article |
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| language | English |
| publishDate | 2024-12-01 |
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| series | Molecules |
| spelling | doaj-art-4a40028014174cd184302d2ba5edb5772025-08-20T02:36:11ZengMDPI AGMolecules1420-30492024-12-013015810.3390/molecules30010058FXR Activation Accelerates Early Phase of Osteoblast Differentiation Through COX-2-PGE<sub>2</sub>-EP4 Axis in BMP-2-Induced Mouse Mesenchymal Stem CellsKo Fujimori0Yusuke Iguchi1Yukiko Yamashita2Keigo Gohda3Naoki Teno4Department of Pathobiochemistry, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki 569-1094, JapanFaculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1, Hirokoshingai, Kure 737-0112, JapanFaculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1, Hirokoshingai, Kure 737-0112, JapanComputer-Aided Molecular Modeling Research Center, Kansai (CAMM-Kansai), 3-32-302, Tsuto-Otsuka, Nishinomiya 663-8241, JapanGraduate School of Pharmaceutical Sciences, Hiroshima International University, 5-1-1, Hirokoshingai, Kure 737-0112, JapanFarnesoid X receptor (FXR), a nuclear receptor, is expressed in calvaria and bone marrow stromal cells and plays a role in bone homeostasis. However, the mechanism of FXR-activated osteoblast differentiation remains unclear. In this study, we investigated the regulatory mechanism underlying FXR-activated osteoblast differentiation using bone morphogenetic protein-2 (BMP-2)-induced mouse ST-2 mesenchymal stem cells. We also synthesized a novel FXR agonist, <b>FLG390</b>, and compared its biological effects in osteoblast differentiation with a known FXR agonist, chenodeoxycholic acid (CDCA). As an FXR agonist, <b>FLG390</b> accelerated osteoblast differentiation to a comparable extent with CDCA, enhancing alkaline phosphatase (ALP) activity and the expression of osteoblast differentiated-related genes such as ALP, collagen type 1 α1 chain (COL1A1), and runt-related transcription factor 2 (RUNX2). FXR activation elevated the expression of cyclooxygenase (COX)-2 and the production of prostaglandin (PG) E<sub>2</sub> in the early phase of osteoblast differentiation. A selective COX-2 inhibitor and an antagonist of EP4 receptors, one of PGE<sub>2</sub> receptors, partially suppressed FXR-activated osteoblast differentiation. Moreover, treatment with either inhibitor during the first 6 h after initiating osteoblast differentiation repressed FXR-activated osteoblast differentiation to the same extent as did the treatment for 6 d. Therefore, a novel FXR agonist, <b>FLG390,</b> exhibited potency comparable to CDCA. FXR activation promoted the early phase of osteoblast differentiation via the COX-2-PGE<sub>2</sub>-EP4 axis, representing a potential target for control of bone metabolism.https://www.mdpi.com/1420-3049/30/1/58mesenchymal stem cellsosteoblastsFXRCOX-2PGE<sub>2</sub> |
| spellingShingle | Ko Fujimori Yusuke Iguchi Yukiko Yamashita Keigo Gohda Naoki Teno FXR Activation Accelerates Early Phase of Osteoblast Differentiation Through COX-2-PGE<sub>2</sub>-EP4 Axis in BMP-2-Induced Mouse Mesenchymal Stem Cells Molecules mesenchymal stem cells osteoblasts FXR COX-2 PGE<sub>2</sub> |
| title | FXR Activation Accelerates Early Phase of Osteoblast Differentiation Through COX-2-PGE<sub>2</sub>-EP4 Axis in BMP-2-Induced Mouse Mesenchymal Stem Cells |
| title_full | FXR Activation Accelerates Early Phase of Osteoblast Differentiation Through COX-2-PGE<sub>2</sub>-EP4 Axis in BMP-2-Induced Mouse Mesenchymal Stem Cells |
| title_fullStr | FXR Activation Accelerates Early Phase of Osteoblast Differentiation Through COX-2-PGE<sub>2</sub>-EP4 Axis in BMP-2-Induced Mouse Mesenchymal Stem Cells |
| title_full_unstemmed | FXR Activation Accelerates Early Phase of Osteoblast Differentiation Through COX-2-PGE<sub>2</sub>-EP4 Axis in BMP-2-Induced Mouse Mesenchymal Stem Cells |
| title_short | FXR Activation Accelerates Early Phase of Osteoblast Differentiation Through COX-2-PGE<sub>2</sub>-EP4 Axis in BMP-2-Induced Mouse Mesenchymal Stem Cells |
| title_sort | fxr activation accelerates early phase of osteoblast differentiation through cox 2 pge sub 2 sub ep4 axis in bmp 2 induced mouse mesenchymal stem cells |
| topic | mesenchymal stem cells osteoblasts FXR COX-2 PGE<sub>2</sub> |
| url | https://www.mdpi.com/1420-3049/30/1/58 |
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