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Open Access Research article

Hypoxia upregulates angiogenesis and synovial cell migration in rheumatoid arthritis

Mohammed A Akhavani12, Leigh Madden1, Ian Buysschaert13, Branavan Sivakumar12, Norbert Kang2 and Ewa M Paleolog1*

Author Affiliations

1 Kennedy Institute of Rheumatology, Imperial College Faculty of Medicine, Aspenlea Road, London W6 8LH, UK

2 Royal Free Hospital, Pond Street, London NW3 2QG, UK

3 Vesalius Research Center, VIB, Katholieke Universiteit Leuven, Campus Gasthuisberg, Herestraat 49, box 912, 9th floor, 3000 Leuven, Belgium

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Arthritis Research & Therapy 2009, 11:R64  doi:10.1186/ar2689

Published: 8 May 2009

Abstract

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 (MMPs) and angiogenic factors were measured, while RNA was extracted for PCR quantification of MMPs/tissue inhibitors of MMP (TIMPs) 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 MMPs 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 proangiogenic and proinvasive, thus leading to the debilitating features characteristic of RA.