Heterotypic contact reveals a COX-2-mediated suppression of osteoblast differentiation by endothelial cells: A negative modulatory role for prostanoids in VEGF-mediated cell: cell communication?

Clarkin, C E; Garonna, E; Pitsillides, A A; Wheeler-Jones, C P D

Abstract

in bone, angiogenesis most be initiated appropriately, but limited once remodelling or repair is complete. Our recent findings have Supported a role for prostaglandins (PG), known modulators of osteoblast (OB) and endothelial cell (EC) behaviour, in facilitating VEGF-mediated paracrine communication from OBs to 'remotely located' ECs, but the mechanism(s) regulating OB:EC crosstalk when these cells are closely opposed are undefined. In this study we have examined: (i) the effects of exogenous PGE(2) on VEGF-driven events in ECs, and (it) the role of endogenous COX-2-derived prostanoids in mediating communication between intimately opposed OBs and ECs in direct contact. Exposure of ECs to PGE(2) increased ERK1/2 phosphorylation, COX-2 induction, 6-keto-PGF(1 alpha),, release and EC proliferation. In contrast, PGE2 attenuated VEGF(165)- induced VEGFR2/Flk1 phosphorylation, ERK1/2 activation and proliferation of ECs, Suggesting that exogenous PGE2 restricts the actions of VEGF. However, the COX-2-selective inhibitor, NS398, also attenuated VEGF-induced proliferation, implying a distinct role for endogenous COX-2 activity in regulating EC behaviour. To examine the effect of OB:EC proximity and the role of COX-2 products further, we Used a confrontational co-culture model. These studies showed that COX-2 blockade with NS398 enhanced EC-dependent increases in OB differentiation, that this effect was reversed by exogenous PGH(2) (immediate COX-2 product), and that exogenous VEGF did not influence EC-dependent OB differentiation under these conditions. Our findings indicate that locally produced prostanoids may serve distinct roles depending,g on OB:EC proximity and negatively modulate VEGF-mediated changes in EC behaviour when these cells are closely opposed to control angiogenesis during bone (re)modelling. (C) 2008 Elsevier Inc. All rights reserved.

Citation

Clarkin, C. E., Garonna, E., Pitsillides, A. A., & Wheeler-Jones, C. P. D. Heterotypic contact reveals a COX-2-mediated suppression of osteoblast differentiation by endothelial cells: A negative modulatory role for prostanoids in VEGF-mediated cell: cell communication?. Experimental Cell Research, 314(17), 3152-3161. https://doi.org/10.1016/j.yexcr.2008.07.027

• Journal Article Type: Article
• Deposit Date: Nov 11, 2014
• Journal: Experimental Cell Research
• Print ISSN: 0014-4827
• Publisher: Elsevier
• Volume: 314
• Issue: 17
• Pages: 3152-3161
• DOI: https://doi.org/10.1016/j.yexcr.2008.07.027
• Public URL: https://rvc-repository.worktribe.com/output/1428887
• Additional Information: Corporate Creators : King's