Phosphate-induced activation of VEGFR2 leads to caspase-9-mediated apoptosis of hypertrophic chondrocytes

• Published in: iScience 2023-09, Vol.26 (9), p.107548, Article 107548
• Main Authors: Yadav, Prem Swaroop, Papaioannou, Garyfallia, Kobelski, Margaret M., Demay, Marie B.
• Format: Article
• Language: English
• Subjects: Cell biology; Molecular biology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.107548

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. [Display omitted] •VEGFR2 mediates the actions of Pi on hypertrophic chondrocyte apoptosis•VEGFR2 ligands activate hypertrophic chondrocyte apoptosis•Pi increases the bioavailability of VEGF ligands in cultured hypertrophic chondrocytes•Dietary phosphate restriction exacerbates the growth plate defects in VEGFR2 KO mice Molecular biology; Cell biology