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Open Access Research article

Hyaluronan modulates accumulation of hypoxia-inducible factor-1 alpha, inducible nitric oxide synthase, and matrix metalloproteinase-3 in the synovium of rat adjuvant-induced arthritis model

Li-Wei Chou123, John Wang45, Pei-Lin Chang1 and Yueh-Ling Hsieh1*

Author Affiliations

1 Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University, 91 Hsueh-Shih Road, Taichung, Taiwan 40202, Republic of China

2 Department of Physical Medicine and Rehabilitation, China Medical University Hospital, 2 Yuh-Der Road, Taichung, Taiwan 40447, Republic of China

3 School of Chinese Medicine, China Medical University, 91 Hsueh-Shih Road, Taichung, Taiwan 40202, Republic of China

4 Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, 160, Sec. 3, Chung-Kang Road, Taichung, Taiwan 40705, Republic of China

5 Institute of Biomedical Nutrition, Hungkuang University, 34 Chung-Chie Road, Taichung, Taiwan 40443, Republic of China

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Arthritis Research & Therapy 2011, 13:R90  doi:10.1186/ar3365

Published: 16 June 2011

Abstract

Introduction

Hypoxia is a feature of the inflamed synovium in rheumatoid arthritis (RA). Intra-articular injection of hyaluronan (HA) may be considered a potential way to treat RA. However, the exact molecular mechanism of HA on decreased cellular responses to hypoxic environment is unclear. The present study has been designed to use the adjuvant-induced arthritis model to examine the effects of HA on the changes of immunohistochemical expressions of hypoxia-inducible factor-1alpha (HIF-1alpha), inducible nitric oxide synthase (iNOS), and matrix metalloproteinase-3 (MMP3) in the synovial tissues at the early phase of arthritic inflammation.

Methods

Monoarthritis was induced in adult male Sprague-Dawley (250-300 g) via intraarticular injection of complete Freund's adjuvant (CFA) into the tibiotarsal joint. The CFA-induction arthritis animals were divided into three groups: treatment (intraarticular injection of HA), placebo (intraarticular injection of saline) and controls (no treatments). Functional evaluations of edema and pain behavior, histology, and HIF-1alpha, iNOS, and MMP3 immunohistochemistry were performed before, after the first injection, three injections, and on the follow-up injection of the treatments.

Results

Intra-articular injection of HA also significantly suppressed the mechanical allodynia (p < 0.001) and overexpressions of HIF-1alpha (p < 0.001), iNOS (p = 0.004) and MMP3 (p < 0.001) immunoreactivity in synovium.

Conclusions

This study demonstrated that early intervention of HA is an effective protection against accumulation of inflammation-induced HIF-1alpha, iNOS, and MMP3 to limit erosive damage in CFA-induced model of arthritis.