Premium
Parathyroid hormone‐related protein (107–139) increases human osteoblastic cell survival by activation of vascular endothelial growth factor receptor‐2
Author(s) -
Alonso Verónica,
de Gortázar Arancha R.,
Ardura Juan A.,
AndradeZapata Irene,
AlvarezArroyo M. Victoria,
Esbrit Pedro
Publication year - 2008
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21547
Subject(s) - parathyroid hormone related protein , mapk/erk pathway , endocrinology , medicine , vascular endothelial growth factor , parathyroid hormone , transfection , osteoblast , receptor , protein kinase b , kinase insert domain receptor , chemistry , tyrosine phosphorylation , protein kinase a , cancer research , phosphorylation , biology , cell culture , microbiology and biotechnology , vascular endothelial growth factor a , calcium , biochemistry , genetics , in vitro , vegf receptors
Parathyroid hormone‐related protein (PTHrP) (107–139), in contrast to the N‐terminal fragment PTHrP (1–36), has been shown to interact with the vascular endothelial growth factor (VEGF) system to modulate human osteoblast differentiation. In this study, we evaluated whether this interaction might affect human osteoblastic cell survival. Pre‐incubation with PTHrP (107–139) for 1–24 h dose‐dependently (0.1–100 nM) inhibited dexamethasone‐ or etoposide‐induced cell death in human osteoblastic MG‐63 cells and human osteoblast‐like cells from trabecular bone. This effect, but not that elicited by PTHrP (1–36), was abolished by the VEGF receptor (VEGFR)‐2 inhibitors SU5614 and SU1498 or VEGFR‐2 siRNA transfection in these cells. PTHrP (107–139), but not PTHrP (1–36), at 100 nM, rapidly (within 2 min) increased VEGFR‐2 tyrosine‐phosphorylation in MG‐63 cells; an effect unaffected by several inhibitors of metalloproteinases, neutralizing VEGF 165 or VEGFR‐2 antibodies, or the VEGF binding inhibitor CBO‐PP1. The latter two antagonists also failed to affect 125 I‐[Tyr 116 ] PTHrP (107–115) binding to these cells. Consistent with its effect on VEGFR‐2 activation, PTHrP (107–139) rapidly induced extracellular signal‐regulated kinase (ERK) 1/2 and Akt activaton, and both ERK and phosphatidylinsositol‐3 kinase (PI3K) inhibitors abolished its pro‐survival effect in human osteoblastic cells. In addition, SU5614 and the latter two types of inhibitors abrogated Runx2 activation by this peptide in MG‐63 cells. Transfection with a dominant‐negative Runx2 construct abolished the pro‐survival effect of PTHrP (107–139), associated with a decrease in Bcl‐2/Bax protein ratio. Our findings demonstrate that PTHrP (107–139) interacts with VEGFR‐2 to promote human osteoblastic cell survival by a mechanism involving Runx2 activation. J. Cell. Physiol. 217: 717–727, 2008. © 2008 Wiley‐Liss, Inc.