Rheumatol Int (2007) 27:1099–1111 DOI 10.1007/s00296-007-0346-1 123 ORIGINAL ARTICLE Intra-articular injection of hyaluronate and indomethacin in rabbits with antigen-induced arthritis Yow-Jen Lo · Ming-Thau Sheu · Wen-Chi Tsai · Yun-Ho Lin · Jau-Le Li · Yu-Chih Liang · Chi-Ching Chang · Ming-Shium Hsieh · Chien-Ho Chen Received: 20 July 2006 / Accepted: 3 March 2007 / Published online: 14 April 2007  Springer-Verlag 2007 Abstract Combined eVects of hyaluronate and indometh- acin in the treatment of rabbits with antigen-induced arthritis (AIA) were evaluated by assessing joint swelling, C-reactive protein (CRP) and prostaglandin E 2 (PGE 2 ) levels with periodic intra-articular (ia) injections of hyalur- onate alone (HA group) and with either a low or high concentration of indomethacin (LI-HA or HI-HA group). End-point analyses included matrix metalloproteinases-3 (MMP-3) activity and macroscopic and histological joint examinations. Results demonstrated that treatment in LI-HA and HI-HA groups resulted in statistically signiWcant suppression of CRP, PGE 2, and MMP-3 in comparison with those of HA group. Inhibition of serum CRP was only observed in LI-HA group. The order of serum MMP-3 inhibition was LI-HA>HI-HA>HA. Based on macroscopic and histological analyses of pannus formation, hyperplasia, inXammation, joint leakage and erosion, and loss of proteo- glycan, the only statistically signiWcant improvement was shown in LI-HA group compared to HA group and HI-HA group compared to control group. Keywords Antigen-induced arthritis · Hyaluronate · Indomethacin · CRP · PGE 2 · MMP Introduction Arthritis is a chronic multifactorial disease induced when the immune system attacks and begins degrading the body’s joints. Common underlying symptoms of the above clinical manifestations include inXammation, destruction of cartilage and soft tissue, and dysfunction of the joints [1–3]. Therapeutic approaches using an elastoviscous HA solution and HA derivatives (hylans) for treatment of arthritis pain are based on the Wnding that long-lasting analgesia can be achieved in joints of arthritic horses by replacing patho- logic synovial Xuid with a highly puriWed HA solution of normal elastoviscosity but signiWcantly greater concentra- tion than that of healthy joint Xuid. Hyaluronic acid (HA) is an abundant non-sulfated glycosaminoglycan component of synovial Xuid and extracellular matrices. In normal human synovial Xuid, the molecular weight (MW) of HA is (6–7) £ 10 6 Da, and the concentration is 2–4 mg/ml. HA prepara- tions appear to be quite safe, with local reactions at the injection site (e.g., pain and swelling) generally being mild and transient [4]. As a result of this discovery, highly Y.-J. Lo · M.-T. Sheu College of Pharmacy, Taipei Medical University, Taipei, Taiwan, ROC W.-C. Tsai Department of Orthopedic Surgery, Min-Sheng Healthcare, Taoyuan, Taiwan, ROC Y.-H. Lin Department of Pathology, Taipei Medical University, Taipei, Taiwan, ROC J.-L. Li · M.-S. Hsieh Department of Orthopedics and Traumatology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan, ROC Y.-C. Liang · C.-H. Chen (&) School of Medical Technology, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 110, Taiwan, ROC e-mail: chenchho@tmu.edu.tw C.-C. Chang Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan, ROC