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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?

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?
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?
In bone, angiogenesis must 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 (ii) 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(1alpha) release and EC proliferation. In contrast, PGE(2) attenuated VEGF(165)-induced VEGFR2/Flk1 phosphorylation, ERK1/2 activation and proliferation of ECs, suggesting that exogenous PGE(2) 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 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.
vegf, vegfr, pge2, cox-2, osteoblast, endothelial cell, cell proliferation, cell differentiation, cell: cell communication
0014-4827
3152-3161
Clarkin, Claire E.
05cd2a88-1127-41aa-a29b-7ac323b4f3c9
Garonna, Elena
f6da72a4-f24b-4fc0-bc4d-16e3dc58eeb2
Pitsillides, Andrew A.
e4ebf5b6-5e10-47dd-8bc9-f3baa8e29707
Wheeler-Jones, Caroline P.D.
d2980530-482b-438f-81ec-e7a2b4359381
Clarkin, Claire E.
05cd2a88-1127-41aa-a29b-7ac323b4f3c9
Garonna, Elena
f6da72a4-f24b-4fc0-bc4d-16e3dc58eeb2
Pitsillides, Andrew A.
e4ebf5b6-5e10-47dd-8bc9-f3baa8e29707
Wheeler-Jones, Caroline P.D.
d2980530-482b-438f-81ec-e7a2b4359381

Clarkin, Claire E., Garonna, Elena, Pitsillides, Andrew A. and Wheeler-Jones, Caroline P.D. (2008) 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. (doi:10.1016/j.yexcr.2008.07.027). (PMID:18718465)

Record type: Article

Abstract

In bone, angiogenesis must 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 (ii) 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(1alpha) release and EC proliferation. In contrast, PGE(2) attenuated VEGF(165)-induced VEGFR2/Flk1 phosphorylation, ERK1/2 activation and proliferation of ECs, suggesting that exogenous PGE(2) 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 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.

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e-pub ahead of print date: 7 August 2008
Published date: 15 October 2008
Keywords: vegf, vegfr, pge2, cox-2, osteoblast, endothelial cell, cell proliferation, cell differentiation, cell: cell communication
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 204381
URI: https://eprints.soton.ac.uk/id/eprint/204381
ISSN: 0014-4827
PURE UUID: 13b30d2d-283d-42fe-9fd8-4c04ebe3d2b2

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Date deposited: 28 Nov 2011 12:02
Last modified: 28 Oct 2019 21:32

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