Raf kinases are essential for phosphate induction of ERK1/2 phosphorylation in hypertrophic chondrocytes and normal endochondral bone development

Autor(en)

Garyfallia Papaioannou, Elizabeth T. Petit, Eva S. Liu, Manuela Baccarini, Catrin Pritchard, Marie B. Demay

Abstrakt

Hypophosphatemia causes rickets by impairing hypertrophic chondrocyte apoptosis. Phosphate induction of MEK1/2-ERK1/2 phosphorylation in hypertrophic chondrocytes is required for phosphate-mediated apoptosis and growth plate maturation. MEK1/2 can be activated by numerous molecules including Raf isoforms. A- and B-Raf ablation in chondrocytes does not alter skeletal development, whereas ablation of C-Raf decreases hypertrophic chondrocyte apoptosis and impairs vascularization of the growth plate. However, ablation of C-Raf does not impair phosphate-induced ERK1/2 phosphorylation in vitro, but leads to rickets by decreasing VEGF protein stability. To determine whether Raf isoforms are required for phosphateinduced hypertrophic chondrocyte apoptosis, mice lacking all three Raf isoforms in chondrocytes were generated. Raf deletion caused neonatal death and a significant expansion of the hypertrophic chondrocyte layer of the growth plate, accompanied by decreased cleaved caspase-9. This was associated with decreased phospho-ERK1/2 immunoreactivity in the hypertrophic chondrocyte layer and impaired vascular invasion. These data further demonstrated that Raf kinases are required for phosphate-induced ERK1/2 phosphorylation in cultured hypertrophic chondrocytes and perform essential, but partially redundant roles in growth plate maturation.

Organisation(en)

Department für Mikrobiologie, Immunbiologie und Genetik

Externe Organisation(en)

Harvard University, University of Leicester, Massachussetts General Hospital

Journal

Journal of Biological Chemistry

Band

292

Seiten

3164-3171

Anzahl der Seiten

8

ISSN

0021-9258

DOI

https://doi.org/10.1074/jbc.M116.763342

Publikationsdatum

02-2017

Peer-reviewed

Ja

ÖFOS 2012

301306 Medizinische Molekularbiologie, 106023 Molekularbiologie

ASJC Scopus Sachgebiete

Biochemistry, Molecular Biology, Cell Biology

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/raf-kinases-are-essential-for-phosphate-induction-of-erk12-phosphorylation-in-hypertrophic-chondrocytes-and-normal-endochondral-bone-development(e489dc2c-813b-4622-a932-949b3cdcc2b3).html