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Hyaluronan inhibits p38 mitogen-activated protein kinase via the receptors in rheumatoid arthritis chondrocytes stimulated with fibronectin fragment

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Abstract

This study was aimed to examine the inhibitory mechanism of high molecular weight hyaluronan (HA) on nitric oxide (NO) production by NH2-terminal heparin-binding fibronectin fragment (FN-f) in rheumatoid arthritis (RA) chondrocytes. When the RA cartilage explants or the isolated RA chondrocytes in monolayer were incubated with FN-f, the fragment stimulated NO production with induction of inducible nitric oxide synthase (iNOS) and activation of p38 mitogen-activated protein kinase. Pretreatment with 2,700 kDa HA resulted in significant suppression of FN-f-stimulated NO production in RA cartilage as well as in chondrocyte monolayer cultures in association with iNOS down-regulation. Inhibition studies with p38 inhibitor indicated the requirement of p38 for FN-f-induced NO production. HA suppressed p38 activation by the FN-f, leading to a decrease in NO production. Immunofluorescence cytochemistry revealed HA association with intercellular adhesion molecule-1 (ICAM-1) and CD44. While the individual antibody to ICAM-1 or CD44 partially reversed HA effect on the FN-f action, both antibodies in combination completely blocked the HA effect. The present study clearly demonstrated that the high molecular weight of HA suppressed the FN-f-activated p38 via ICAM-1 and the CD44 in RA chondrocytes. HA could down-regulate the catabolic action of FN-f in RA joints through the mechanism demonstrated in this study.

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Acknowledgments

This study was partly supported by the grant from Chugai Pharmaceutical Company.

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Authors and Affiliations

  1. Department of Sports Medicine, Faculty of Budo and Sport Studies, Tenri University, 80 Tainosho-cho, Tenri, Nara, 632-0071, Japan

    Tadashi Yasuda

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  1. Tadashi Yasuda
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Correspondence to Tadashi Yasuda.

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Yasuda, T. Hyaluronan inhibits p38 mitogen-activated protein kinase via the receptors in rheumatoid arthritis chondrocytes stimulated with fibronectin fragment. Clin Rheumatol 29, 1259–1267 (2010). https://doi.org/10.1007/s10067-010-1512-5

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  • DOI: https://doi.org/10.1007/s10067-010-1512-5

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