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Calcineurin Is Expressed and Plays a Critical Role in Inflammatory Arthritis¹

Seung-Ah Yoo^*, Bo-Hyoung Park^*, Gyeong-Sin Park, Hae-Seok Koh, Mi-Sook Lee, Sung Ho Ryu, Keiji Miyazawa^¶, Sung-Hwan Park^*, Chul-Soo Cho^* and Wan-Uk Kim^2,*

^* Department of Internal Medicine, Department of Clinical Pathology, and Department of Orthopedic Surgery, Catholic University of Korea, Seoul, Korea; Department of Life Science, Pohang University of Science and Technology, Pohang, Korea; and ^¶ Kissei Pharmaceutical, Nagano, Japan

Calcineurin is a calcium-activated phosphatase to mediate lymphocyte activation and neuron signaling, but its role in inflammatory arthritis remains largely unknown. In this study, we demonstrate that calcineurin was highly expressed in the lining layer, infiltrating leukocytes, and endothelial cells of rheumatoid synovium. The basal expression levels of calcineurin were higher in the cultured synoviocytes of rheumatoid arthritis patients than those of osteoarthritis patients. The calcineurin activity in the synoviocytes was increased by the stimulation with proinflammatory cytokines such as IL-1 and TNF-. Moreover, rheumatoid arthritis synoviocytes had an enlarged intracellular Ca²⁺ store and showed a higher degree of [Ca²⁺]_i release for calcineurin activity than osteoarthritis synoviocytes when stimulated with either TNF- or phorbol myristate acetate. IL-10, an anti-inflammatory cytokine, failed to increase the Ca²⁺ and calcineurin activity. The targeted inhibition of calcineurin by the overexpression of calcineurin-binding protein 1, a natural calcineurin antagonist, inhibited the production of IL-6 and matrix metalloproteinase-2 by rheumatoid synoviocytes in a similar manner to the calcineurin inhibitor, cyclosporin A. Moreover, the abundant calcineurin expression was found in the invading pannus in the joints of mice with collagen-induced arthritis. In these mice, calcineurin activity in the cultured synovial and lymph node cells correlated well with the severity of arthritis, but which was suppressed by cyclosporin A treatment. Taken together, our data suggest that the abnormal activation of Ca²⁺ and calcineurin in the synoviocytes may contribute to the pathogenesis of chronic arthritis and thus provide a potential target for controlling inflammatory arthritis.

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The JI 2006 177: 2033-2034. [Full Text]