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-1β and TNF-α. 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-α 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.

Objective. To determine whether intracellular calcineurin (Cn), a calcium-activated phosphatase, regulates the anabolic and catabolic activities of chondrocytes, and is a potential target in the treatment of osteoarthritis (OA).Methods. CnA expression was examined in cartilage tissue samples and cultured chondrocytes from OA patients, using immunohistochemistry and Western blot analysis, respectively. Concentrations of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases 1 (TIMP-1) in the culture supernatants were determined using enzyme-linked immunosorbent assay. Levels of nitric oxide (NO) and type II collagen (CII) were measured using the Griess reaction and Western blot analysis, respectively. In addition, the pathologic role of Cn was examined in an in vivo model in which experimental OA was induced in mice by injecting type VII collagenase into the knee joints.Results. CnA was highly expressed in the chondrocytes of lesional OA cartilage. Cyclosporin A (CSA), a Cn inhibitor, inhibited spontaneous and interleukin-1␤-stimulated production of NO, MMP-1, and MMP-3 in chondrocytes. However, CSA increased the levels of production of CII, TIMP-1, and transforming growth factor ␤. Similar changes in MMP-1, NO, and CII expression levels in chondrocytes were observed after the targeted inhibition of Cn by overexpression of calcineurin binding protein 1, a natural Cn antagonist. Moreover, in the mouse model, animals treated with CSA showed a significant decrease in both the extent and the severity of cartilage damage, which were assessed macroscopically and microscopically, compared with vehicle-treated animals.Conclusion. These results suggest that CnA is critically involved in the catabolic and anabolic activities of chondrocytes as well as in the progression of experimental OA. Targeted inhibition of CnA may be an effective treatment strategy for OA.The failure of chondrocytes to maintain cartilage integrity is a key event leading to joint destruction in many arthritic conditions, including rheumatoid arthritis (RA), osteoarthritis (OA), and septic arthritis (1,2). Chondrocytes respond to a variety of stimuli, including proinflammatory cytokines and mechanical loading, by increasing the concentration of cartilage degradative enzymes and catabolic mediators. A disturbance in the regulation of the anabolic and catabolic activities of chondrocytes can result in a net loss of cartilage matrix components. Regardless of the initiating stimuli, the key process in cartilage degradation is similar, involving specific matrix metalloproteinases (MMPs), nitric oxide (NO), and aggrecanases, which are members of the ADAMTS family (3). Previous studies have demonstrated that interleukin-1␤ (IL-1␤) and tumor necrosis factor ␣ (TNF␣) also play key roles in cartilage degradation by stimulating their own production and inducing chondrocytes to produce MMPs and NO (4,5).

Pachymeningitis is a very rare neurologic manifestation of polyarteritis nodosa (PAN). This report describes a case of acute pachymeningitis that was, initially, misdiagnosed as subdural hematoma on the brain CT of a patient with PAN. A 45-year-old man, who had been diagnosed as having PAN 6 months previously, came back to the emergency room with complaints of sudden headache, nausea, vomiting, and diplopia for 3 days before his hospital admission. Initially, the noncontrast enhanced brain CT findings showed high densities in the bilateral tentorial and posterior parafalcial area, which suggested a small amount of subdural hematoma. However, the subsequent MRI findings revealed pachymeningitis of the bilateral tentoria and falx. He was treated with high-dose steroid and cyclophosphamide pulse therapy. Thereafter, his symptoms gradually resolved.

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