Open Access Highly Accessed Research article

Intra-articular injections of high-molecular-weight hyaluronic acid have biphasic effects on joint inflammation and destruction in rat antigen-induced arthritis

Andreas Roth1*, Jürgen Mollenhauer12, Andreas Wagner1, Reneè Fuhrmann1, Albrecht Straub1, Rudolf A Venbrocks1, Peter Petrow3, Rolf Bräuer3, Harald Schubert4, Jörg Ozegowski5, Gundela Peschel6, Peter J Müller6 and Raimund W Kinne7

Author Affiliations

1 Department of Orthopaedics, 'Rudolf-Elle' Hospital, Friedrich Schiller University Jena, Eisenberg, Germany

2 Department of Biochemistry, Rush Medical College Head, Chicago, Illinois, USA

3 Institute of Pathology, Friedrich Schiller University Jena, Germany

4 Institute of Animal Studies, Friedrich Schiller University Jena, Germany

5 Institute of Biochemistry 2, Friedrich Schiller University Jena, Germany

6 Hans Knoell Institute for Natural Products Research, Jena, Germany

7 Experimental Rheumatology Unit, Friedrich Schiller University Jena, Germany

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Arthritis Research & Therapy 2005, 7:R677-R686  doi:10.1186/ar1725

Published: 31 March 2005

Abstract

To assess the potential use of hyaluronic acid (HA) as adjuvant therapy in rheumatoid arthritis, the anti-inflammatory and chondroprotective effects of HA were analysed in experimental rat antigen-induced arthritis (AIA). Lewis rats with AIA were subjected to short-term (days 1 and 8, n = 10) or long-term (days 1, 8, 15 and 22, n = 10) intra-articular treatment with microbially manufactured, high-molecular-weight HA (molecular weight, 1.7 × 106 Da; 0.5 mg/dose). In both tests, 10 buffer-treated AIA rats served as arthritic controls and six healthy animals served as normal controls. Arthritis was monitored by weekly assessment of joint swelling and histological evaluation in the short-term test (day 8) and in the long-term test (day 29). Safranin O staining was employed to detect proteoglycan loss from the epiphyseal growth plate and the articular cartilage of the arthritic knee joint. Serum levels of IL-6, tumour necrosis factor alpha and glycosaminoglycans were measured by ELISA/kit systems (days 8 and 29). HA treatment did not significantly influence AIA in the short-term test (days 1 and 8) but did suppress early chronic AIA (day 15, P < 0.05); however, HA treatment tended to aggravate chronic AIA in the long-term test (day 29). HA completely prevented proteoglycan loss from the epiphyseal growth plate and articular cartilage on day 8, but induced proteoglycan loss from the epiphyseal growth plate on day 29. Similarly, HA inhibited the histological signs of acute inflammation and cartilage damage in the short-term test, but augmented acute and chronic inflammation as well as cartilage damage in the long-term test. Serum levels of IL-6, tumour necrosis factor alpha, and glycosaminoglycans were not influenced by HA. Local therapeutic effects of HA in AIA are clearly biphasic, with inhibition of inflammation and cartilage damage in the early chronic phase but with promotion of joint swelling, inflammation and cartilage damage in the late chronic phase.