MSX2 promotes osteogenesis and suppresses adipogenic differentiation of multipotent mesenchymal progenitors
In the aorta, diabetes activates an osteogenic program that includes expression of bone morphogenetic protein-2 (BMP2) and the osteoblast homeoprotein Msx2. To evaluate BMP2-Msx2 signaling in vascular calcification, we studied primary aortic myofibroblasts. These cells express vascular smooth muscle cell (VSMC) markers, respond to BMP2 by up-regulating Msx2, and undergo osteogenic differentiation with BMP2 treatment or transduction with a virus encoding Msx2. The osteoblast factor osterix (Osx) is up-regulated 10-fold by Msx2, but Runx2 mRNA is unchanged; the early osteoblast marker alkaline phosphatase increases 50-fold with mineralized nodule formation enhanced 30-fold. Adipocyte markers are concomitantly suppressed. To better understand Msx2 actions on osteogenesis versus adipogenesis, mechanistic studies were extended to C3H10T1/2 mesenchymal cells. Msx2 enhances osteogenic differentiation in synergy with BMP2. Osteogenic actions depend upon intrinsic Msx2 DNA binding; the gain-of-function variant Msx2(P148H) directs enhanced mineralization, whereas the binding-deficient variant Msx2(T147A) is inactive. Adipogenesis (lipid accumulation, Pparg expression) is inhibited by Msx2. By contrast, suppression of adipogenesis does not require Msx2 DNA binding; inhibition occurs in part via protein-protein interactions with C/EBPalpha that control Pparg transcription. Thus, Msx2 regulates osteogenic versus adipogenic differentiation of aortic myofibroblasts. Myofibroblasts capable of both fates can be diverted to the osteogenic lineage by BMP2-Msx2 signaling and contribute to vascular calcification.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2003 |
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| Erschienen: |
2003 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:278 |
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| Enthalten in: |
The Journal of biological chemistry - 278(2003), 46 vom: 14. Nov., Seite 45969-77 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cheng, Su-Li [VerfasserIn] |
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| Anmerkungen: |
Date Completed 24.12.2003 Date Revised 18.03.2022 published: Print-Electronic Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM126772894 |
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| 100 | 1 | |a Cheng, Su-Li |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a MSX2 promotes osteogenesis and suppresses adipogenic differentiation of multipotent mesenchymal progenitors |
| 264 | 1 | |c 2003 | |
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| 500 | |a Date Completed 24.12.2003 | ||
| 500 | |a Date Revised 18.03.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a In the aorta, diabetes activates an osteogenic program that includes expression of bone morphogenetic protein-2 (BMP2) and the osteoblast homeoprotein Msx2. To evaluate BMP2-Msx2 signaling in vascular calcification, we studied primary aortic myofibroblasts. These cells express vascular smooth muscle cell (VSMC) markers, respond to BMP2 by up-regulating Msx2, and undergo osteogenic differentiation with BMP2 treatment or transduction with a virus encoding Msx2. The osteoblast factor osterix (Osx) is up-regulated 10-fold by Msx2, but Runx2 mRNA is unchanged; the early osteoblast marker alkaline phosphatase increases 50-fold with mineralized nodule formation enhanced 30-fold. Adipocyte markers are concomitantly suppressed. To better understand Msx2 actions on osteogenesis versus adipogenesis, mechanistic studies were extended to C3H10T1/2 mesenchymal cells. Msx2 enhances osteogenic differentiation in synergy with BMP2. Osteogenic actions depend upon intrinsic Msx2 DNA binding; the gain-of-function variant Msx2(P148H) directs enhanced mineralization, whereas the binding-deficient variant Msx2(T147A) is inactive. Adipogenesis (lipid accumulation, Pparg expression) is inhibited by Msx2. By contrast, suppression of adipogenesis does not require Msx2 DNA binding; inhibition occurs in part via protein-protein interactions with C/EBPalpha that control Pparg transcription. Thus, Msx2 regulates osteogenic versus adipogenic differentiation of aortic myofibroblasts. Myofibroblasts capable of both fates can be diverted to the osteogenic lineage by BMP2-Msx2 signaling and contribute to vascular calcification | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, P.H.S. | |
| 650 | 7 | |a DNA-Binding Proteins |2 NLM | |
| 650 | 7 | |a Homeodomain Proteins |2 NLM | |
| 650 | 7 | |a MSX2 protein |2 NLM | |
| 650 | 7 | |a RNA, Messenger |2 NLM | |
| 650 | 7 | |a Receptors, Cytoplasmic and Nuclear |2 NLM | |
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| 700 | 1 | |a Charlton-Kachigian, Nichole |e verfasserin |4 aut | |
| 700 | 1 | |a Loewy, Arleen P |e verfasserin |4 aut | |
| 700 | 1 | |a Towler, Dwight A |e verfasserin |4 aut | |
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