Crosstalk between FLS and chondrocytes is regulated by HIF-2alpha-mediated cytokines in arthritis

Rheumatoid arthritis (RA) and osteoarthritis (OA), two common types of arthritis, affect the joints mainly by targeting the synovium and cartilage. Increasing evidence indicates that a significant network connects synovitis and cartilage destruction during the progression of arthritis. We recently demonstrated that hypoxia-inducible factor (HIF)-2alpha causes RA and OA by regulating the expression of catabolic factors in fibroblast-like synoviocytes (FLS) or chondrocytes. To address the reciprocal influences of HIF-2alpha on FLS and chondrocytes, we applied an in vitro co-culture system using a transwell apparatus. When co-cultured with HIF-2alpha-overexpressing chondrocytes, FLS exhibited increased expression of matrix metalloproteinases and inflammatory mediators, similar to the effects induced by tumor-necrosis factor (TNF)-alpha treatment of FLS. Moreover, chondrocytes co-cultured with HIF-2alpha-overexpressing FLS exhibited upregulation of Mmp3 and Mmp13, which is similar to the effects induced by interleukin (IL)-6 treatment of chondrocytes. We confirmed these differential HIF-2alpha-induced effects via distinct secretory mediators using Il6-knockout cells and a TNF-alpha-blocking antibody. The FLS-co-culture-induced gene expression changes in chondrocytes were significantly abrogated by IL-6 deficiency, whereas TNF-alpha neutralization blocked the alterations in gene expression associated with co-culture of FLS with chondrocytes. Our results further suggested that the observed changes might reflect the HIF-2alpha-induced upregulation of specific receptors for TNF-alpha (in FLS) and IL-6 (in chondrocytes). This study broadens our understanding of the possible regulatory mechanisms underlying the crosstalk between the synovium and cartilage in the presence of HIF-2alpha, and may suggest potential new anti-arthritis therapies.

Expression of osteopontin in synovial tissue of rheumatoid arthritis: its relation to disease activity and severity

To demonstrate the expression of osteopontin in synovial tissue of patients with rheumatoid arthritis and to correlate it with disease activity and severity in order to find out its possible role in the pathogenesis of the disease. This study was conducted on 30 RA patients and 10 control subjects with post traumatic knee injury. All patients were subjected to full medical history taking, thorough clinical examination with special attention to articular manifestations [Modified disease activity score] [DAS], and spread severity index [SSI]. Laboratory investigations included: CBC, ESR, CRP and RF. Radiological investigations included: plain x-ray of the affected knee joint using Larsen's score for assessment of joint damage and expression of osteopontin [OPN] in synovial tissues of both patients and controls was determined by immunohistochemical staining of formalin fixed, paraffin embedded synovial tissues. We demonstrated by immunohistochemistry that OPN was detected as brown cytoplasmic staining expressed predominantly in the lining layer of rheumatoid synovium rather than the sublining layer and it was absent in the lymphoid aggregates. In contrast, synovial tissue of the control group showed weak scattered staining for OPN. We found a highly statistical significant difference between RA patients and controls regarding the synovial expression of OPN which was highly associated with the activity. Also, percentage of OPN positive cells was highly associated with the severity of RA assessed clinically by SSI and radiological [p<0.01]. Osteopontin is critically involved in the pathogenesis of both inflammatory and joint-destructive processes in rheumatoid arthritis. OPN may reflect disease activity and can be used as a marker of disease severity

Differential production of IgM and IgA rheumatoid factors in peripheral blood and synovium of patients with pheumatoid arthritis

Total IgM, IgA, and IgM-rheumatoid factor [RF] and IgA-RF were quantitated in the serum and synovial fluid of 35 seropositive and 8 seronegative rheumatoid arthritis [RA] patients, using a sensitive enzyme-linked immunosorbent assay [ELISA]. Mononuclear cells isolated from peripheral blood and synovial fluid of three seropositive patients were also stimulated in vitro with phorbol myristate acetate [PMA] and culture supernatants collected for measurement of total immunoglobulin [Ig] and RF. Our results demonstrated that as a proportion of total Ig, IgM-RF and IgA-RF were significantly higher in the synovial fluid of seropositive patients compared to their serum level. Similar results were observed for in vitro stimulated culture supernatants from the same patients. This difference, however, was not evident in the seronegative group of patients. These results indicate that synovium could be considered as the original site of RF production in seropositive RA patients, and that different repertoires of Blymphocytes may be involved in RF production in peripheral blood and synovial tissues of affected joints

Estudo artroscópico em joelhos de pacientes portadores de artrite reumatóide juvenil do tipo pauciarticular / Arthroscopic study in knees of patients with pauciarticular juvenile rheumatoid arthritis

Os autores estudaram nove pacientes portadores de artrite reumatóide juvenil do tipo pauciarticular, submetidos a artroscopia de joelho, com seguimento médio de 16,5 meses (6 a 54 meses). No estudo morfológico, enfatizaram as diferentes formas de reaçäo sinovial, como também seu padräo heterogênio de distribuiçäo. Näo encontraram relaçäo entre o grau das lesöes condrais e a intensidade da inflamaçäo sinovial. Näo foi encontrada no exame anatomopatológico característica de processo inflamatório agudo. Através da imunofluorescência, detectaron-se depósitos de imunoglobulinas na membrana sinovial e na cartilagem articular. Nesta pesquisa foi valorizada a importância da artroscopia no diagnóstico da artrite reumatóide juvenil do tipo pauciarticular