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

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.