RESEARCH - Hypoxia upregulates angiogenesis and synovial cell migration in RA

[Guest guest]

Arthritis Research & Therapy 2009, 11:R64doi:10.1186/ar2689

Published: 8 May 2009

Research article

Hypoxia upregulates angiogenesis and synovial cell migration in

rheumatoid arthritis

Mohammed A Akhavani , Leigh Madden , Ian Buysschaert , Branavan

Sivakumar , Norbert Kang and Ewa M Paleolog

Abstract (provisional)

Introduction

Rheumatoid arthritis (RA) is characterised by invasion of cartilage,

bone and tendon by inflamed synovium. Previous studies in our

laboratory have shown that hypoxia is a feature of RA synovitis. In

the present study, we investigated the consequences of hypoxia on

angiogenesis and synovial fibroblast migration in RA.

Methods

Synovial tissue was harvested from RA patients, and synovial membrane

cells were cultured under conditions either of hypoxia (1% oxygen) or

normoxia (21% oxygen). Protein levels of matrix metalloproteinases

(MMP) and angiogenic factors were measured, while RNA was extracted

for polymerase chain reaction (PCR) quantification of MMP/tissue

inhibitors of MMP (TIMP) and angiogenic factors. Migration of RA

synovial fibroblasts through collagen, and the effect of RA synovial

cell supernatants in an in vitro angiogenesis assay, were utilised to

determine the functional relevance of changes in mRNA/protein.

Results

We observed upregulation under hypoxic conditions of MMP responsible

for collagen breakdown, specifically collagenase MMP-8, and the

gelatinases MMP-2 and MMP-9, at both mRNA and protein levels.

Increased MT1-MMP mRNA was also observed, but no effect on TIMP-1 or

TIMP-2 was detected. RA fibroblast migration across collagen was

significantly increased under hypoxic conditions, and was dependent on

MMP activity. Furthermore, expression of angiogenic stimuli, such as

vascular endothelial growth factor (VEGF), and VEGF/placental growth

factor heterodimer, was also increased. Crucially, we show for the

first time that hypoxia increased the angiogenic drive of RA cells, as

demonstrated by enhanced blood vessel formation in an in vitro

angiogenesis assay.

Conclusions

Hypoxia may be responsible for rendering RA synovial lining

pro-angiogenic and pro-invasive, thus leading to the debilitating

features characteristic of RA.

************************************************************

Read the full article here:

http://arthritis-research.com/content/pdf/ar2689.pdf

Not an MD