Phosphate-induced activation of VEGFR2 leads to caspase-9-mediated apoptosis of hypertrophic chondrocytes
Summary: Low circulating phosphate (Pi) leads to rickets, characterized by expansion of the hypertrophic chondrocytes (HCs) in the growth plate due to impaired HC apoptosis. Studies in HCs demonstrate that Pi activates the Raf/MEK/ERK1/2 and mitochondrial apoptotic pathways. To determine how Pi acti...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223016255 |
| _version_ | 1797742600309964800 |
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| author | Prem Swaroop Yadav Garyfallia Papaioannou Margaret M. Kobelski Marie B. Demay |
| author_facet | Prem Swaroop Yadav Garyfallia Papaioannou Margaret M. Kobelski Marie B. Demay |
| author_sort | Prem Swaroop Yadav |
| collection | DOAJ |
| description | Summary: Low circulating phosphate (Pi) leads to rickets, characterized by expansion of the hypertrophic chondrocytes (HCs) in the growth plate due to impaired HC apoptosis. Studies in HCs demonstrate that Pi activates the Raf/MEK/ERK1/2 and mitochondrial apoptotic pathways. To determine how Pi activates these pathways, a small-molecule screen was undertaken to identify inhibitors of Pi-induced ERK1/2 phosphorylation in HCs. Vascular endothelial growth factor receptor 2 (VEGFR2) was identified as a target. In vitro studies in HCs demonstrate that VEGFR2 inhibitors block Pi-induced pERK1/2 and caspase-9 cleavage. Like Pi, rhVEGF activates ERK1/2 and caspase-9 in HCs and induces phosphorylation of VEGFR2, confirming that Pi activates this signaling pathway in HCs. Chondrocyte-specific depletion of VEGFR2 leads to an increase in HCs, impaired vascular invasion, and a decrease in HC apoptosis. Thus, these studies define a role for VEGFR2 in transducing Pi signals and mediating its effects on growth plate maturation. |
| first_indexed | 2024-03-12T14:43:01Z |
| format | Article |
| id | doaj.art-70724854ec7c4b9c9c8b830e84b120a2 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-12T14:43:01Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-70724854ec7c4b9c9c8b830e84b120a22023-08-16T04:27:11ZengElsevieriScience2589-00422023-09-01269107548Phosphate-induced activation of VEGFR2 leads to caspase-9-mediated apoptosis of hypertrophic chondrocytesPrem Swaroop Yadav0Garyfallia Papaioannou1Margaret M. Kobelski2Marie B. Demay3Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USAEndocrine Unit, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USAEndocrine Unit, Massachusetts General Hospital, Boston, MA, USAEndocrine Unit, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Corresponding authorSummary: Low circulating phosphate (Pi) leads to rickets, characterized by expansion of the hypertrophic chondrocytes (HCs) in the growth plate due to impaired HC apoptosis. Studies in HCs demonstrate that Pi activates the Raf/MEK/ERK1/2 and mitochondrial apoptotic pathways. To determine how Pi activates these pathways, a small-molecule screen was undertaken to identify inhibitors of Pi-induced ERK1/2 phosphorylation in HCs. Vascular endothelial growth factor receptor 2 (VEGFR2) was identified as a target. In vitro studies in HCs demonstrate that VEGFR2 inhibitors block Pi-induced pERK1/2 and caspase-9 cleavage. Like Pi, rhVEGF activates ERK1/2 and caspase-9 in HCs and induces phosphorylation of VEGFR2, confirming that Pi activates this signaling pathway in HCs. Chondrocyte-specific depletion of VEGFR2 leads to an increase in HCs, impaired vascular invasion, and a decrease in HC apoptosis. Thus, these studies define a role for VEGFR2 in transducing Pi signals and mediating its effects on growth plate maturation.http://www.sciencedirect.com/science/article/pii/S2589004223016255Molecular biologyCell biology |
| spellingShingle | Prem Swaroop Yadav Garyfallia Papaioannou Margaret M. Kobelski Marie B. Demay Phosphate-induced activation of VEGFR2 leads to caspase-9-mediated apoptosis of hypertrophic chondrocytes iScience Molecular biology Cell biology |
| title | Phosphate-induced activation of VEGFR2 leads to caspase-9-mediated apoptosis of hypertrophic chondrocytes |
| title_full | Phosphate-induced activation of VEGFR2 leads to caspase-9-mediated apoptosis of hypertrophic chondrocytes |
| title_fullStr | Phosphate-induced activation of VEGFR2 leads to caspase-9-mediated apoptosis of hypertrophic chondrocytes |
| title_full_unstemmed | Phosphate-induced activation of VEGFR2 leads to caspase-9-mediated apoptosis of hypertrophic chondrocytes |
| title_short | Phosphate-induced activation of VEGFR2 leads to caspase-9-mediated apoptosis of hypertrophic chondrocytes |
| title_sort | phosphate induced activation of vegfr2 leads to caspase 9 mediated apoptosis of hypertrophic chondrocytes |
| topic | Molecular biology Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223016255 |
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