The effects of high molecular weight hyaluronan (HA) on cartilage degeneration were investigated in a partial menisectomy model of osteoarthritis (OA) in the rabbit knee. This study compared HA80 (0.8 x 10(6) Da, 1%), HA190 (1.9 x 10(6) Da, 0.01-1%) and saline. HA (0.1 ml/kg) or saline were injected intra-articularly twice a week immediately after surgery. Degenerative changes in femoral and tibial cartilages were graded histopathologically 2 and 4 weeks after surgery. Two weeks after surgery, HA190, only when used at a 1% concentration, resulted in a dramatic inhibition of cartilage degeneration in both the femoral condyle and the tibial plateau (P < 0.01). Two weeks after surgery, the protection against cartilage degeneration was significantly (P < 0.05) greater with HA190 than with HA80. Four weeks after surgery, only the femoral cartilage degeneration was significantly and similarly inhibited with HA190 (P < 0.01) and HA80 (P < 0.05). Scanning electron micrographs of femoral cartilage showed that cartilage degeneration was less severe with HA190 than with saline. These results might suggest that, in the rabbit model, intra-articular administration of higher molecular weight HA is more effective than lower molecular weight HA in inhibiting cartilage degeneration in early OA.

Objective. To evaluate the efficacy of stromelysin-1 (matrix metalloproteinase-3 [MMP3]) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in serum as markers for joint inflammation in rheumatoid arthritis (RA).Methods. Levels of both macromolecules in sera from 97 healthy controls, 109 patients with RA, and 47 patients with osteoarthritis (OA) were measured by respective 1-step sandwich enzyme immunoassays. In the patients with RA, serum levels of MMP-3 and TIMP-1 were investigated in relation to laboratory and clinical measures of disease activity. In addition, the relationships between serum and synovial fluid (SF) levels in paired samples from individual patients were examined.Results. Serum levels of both MMP-3 and TIMP-1 in RA patients were significantly higher than those in OA patients and in healthy controls (P < 0.001), and were shown to correlate with traditional systemic markers of inflammation including the erythrocyte sedimentation rate and C-reactive protein level, and with the Lansbury articular index. In addition, it was noted that serum levels of MMP-3 correlated with the corresponding values in paired SF samples obtained concurrently from patients with RA (r, = 0.588, P <

Objective. To investigate the roles of SPARC (secreted protein, acidic and rich in cysteine) (osteonectin) in arthritis, using cartilage and synovium specimens and synovial fluids (SF) from patients with rheumatoid arthritis (RA) or osteoarthritis (OA), and to examine the effects of cytokines, growth factors, and hormones on SPARC synthesis by chondrocytes in culture.Methods. SPARC in cartilage and synovium was immunostained with monoclonal antibodies. SPARC synthesis by cultured chondrocytes was measured by Northern blot analysis, immunoblotting, and sandwich enzyme-linked immunosorbent assay.Results. SPARC was identified in numerous chondrocytes in the superficial and middle zones and in Shigeo Nakamura, DDS, Hisashi Satakeda, DDS, Hiroshi Okamoto, DDS, PhD, Mitsuhide Noshiro, PhD, Yukio Kato, DDS, PhD: Hiroshima University, Hiroshima, Japan; Kyouko Kamihagi, PhD, Masahiko Katayama, PhD: Biotechnology Research Laboratones, Takara Shyuzo, Ohtu, Japan; Haiou Pan, DDS: Drug Discovery Research Laboratories, Hoechst Japan Limited, Kawagoe, Japan; Koichiro Takahashi, PhD: Clinical Pharmacology Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Itabashi-ku, Tokyo, Japan; Yasuo Yoshihara, MD, Masayuki Shimmei, MD: National Defense Medical College, Tokorozawa, Japan; Yasunori Okada, MD, PhD: Cancer Research Institute, Kanazawa University, Kanazawa, Japan.Address reprint requests to Yukio Kato, DDS, PhD, Department of Biochemistry, School of Dentistry, Hiroshima University, 1-2-3, Kasumi, Minamiku, Hiroshima City, 734, Japan.Submitted for publication May 11, 1995; accepted in revised form November 6, 1995.regenerating chondrocytes of RA and OA joints, whereas such staining was absent in these zones of normal cartilage, except For weak signals from a few chondrocytes in the deep zone. In addition, SPARC synthesis was enhanced in synovial cells of RA and OA joints. The average SPARC level in SF was 10-fold higher in the RA than in the OA population. In rabbit articular chondrocyte cultures, administration of transforming growth factor pl (TGFp1) and bone morphogenetic protein 2 increased SPARC levels at 24-48 hours, whereas interleukin-lp (IL-lp), IL-la, tumor necrosis factor a, lipopolysaccharide, phorbol myristate acetate, basic fibroblast growth factor, and dexamethasone decreased SPARC levels at 2&72 hours. TGFP increased SPARC messenger RNA (mRNA) levels at 24 hours, whereas IL-IP caused a marked decrease in SPARC mRNA levels at 24 hours. Furthermore, IL-1 decreased the glycosylation of SPARC. Conclusion. These findings suggest that various growth factors and cytokines, including TGFm and IL-lp, regulate the production of SPARC by chondrocytes at pre-and posttranslational levels, and that SPARC synthesis is markedly enhanced in arthritic joints.SPARC (secreted protein, acidic and rich in cysteine) (osteonectin) (BM-40) is a 3543-kd Ca++-binding glycoprotein, which was initially isolated from 539

Objective. To investigate the effects of the interleukind (IL-6) family cytokines, such as IL-6, IL-11, leukemia inhibitory factor (LIF), and oncostatin M (OSM), on the production of tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) in human articular cartilage.Methods. Effects of IL-6 family cytokines and growth factors on TIMP-1 production were studied in human articular chondrocytes, grown as monolayer and cartilage explant culture. TIMP-1 protein levels in the cultured medium were measured by sandwich enzyme immunoassay. TIMP-1 messenger RNA levels in the cultured chondrocytes were analyzed by Northern blotting. Western blot analysis was performed to evaluate the release of matrix metalloproteinases (MMPs) in the cultured medium. Cell proliferation of chondrocytes was determined by 3H-thymidine uptake.Results. IL-6 family cytokines induced TIMP-1 expression in monolayer and explant culture, and the production of TIMP-1 was most stimulated by OSM. In contrast, OSM did not modulate the release of MMPs and cell proliferation.Conclusion. These results suggest that OSM may be characterized as one of the chondroprotective mediators in cartilage destruction.Osteoarthritis (OA) is one of the most common disorders of the human joints. It is characterized by a gradual loss of the extracellular matrices of articular cartilage, such as proteoglycan (PG) and type I1 collagen (1,2). It is well known that extracellular matrices -~-

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