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The aim of this work was to provide an updated review of the mechanisms of action of glucocorticoids. We carried out a MEDLINE search (1970 to present) using "glucocorticoids" as the keyword, both on its own (subheadings: "genetics, immunology, metabolism, physiology, therapeutic use") and combined with "inflammation", "glucocorticoid response element", "gene expression regulation", "NF-kappa B", "transcription factor AP-1", "receptors, glucocorticoid", "chemokines", "cytokines", "cytokine receptors", "resistance", "sensitivity", "annexin-I", "apoptosis", "repressors" and "activators", respectively. Original, partially unpublished data from our research group was also reported. Although we reviewed the sources available, we did not adopt any statistic procedures for data extraction, as the review deals only with basic research. The results of this review indicate that glucocorticoids act through different mechanisms: they can regulate the transcription of a number of genes (genomic mechanisms), interfere with cell activation factors (mechanisms of repression of cell activation factors), and inhibit cell activation via a direct interaction with the cell membrane and/or some of its components (non-genomic mechanisms). There is some evidence that most of the anti-inflammatory effects of glucocorticoids are mediated by repression of transcriptor factors, whereas their metabolic effects appear to be predominantly mediated by genomic mechanisms. This observation has prompted the search for new steroid compounds endowed with more selective anti-inflammatory properties than those currently available. We conclude that better understanding of the mechanisms of action of steroids may result in the development of new molecules with a better risk/benefit ratio.

To verify the distribution of different types of beta 1 integrin on the plasma membrane of chondrocytes and to correlate the pattern of integrin expression to the severity of osteoarthritis (OA).The articular cartilage of ten OA patients who had undergone surgical knee replacement for "genu varum" were studied. The cartilage was separated into three zones that macroscopically and microscopically showed a decreasing degree of anatomic lesions. After enzymatic digestion, the isolated chondrocytes were immediately challenged with monoclonal antibodies against the beta 1, alpha 1-6 and alpha v chains. The phenotypic study was paralleled by a cell cycle analysis performed by flow cytometry on chondrocytes stained with propidium iodide.Chondrocytes isolated from the articular cartilage of osteoarthritic patients expressed, in different percentages, all the alpha chains (alpha 1-6 and alpha v) of the beta 1 integrins. The alpha chain most frequently expressed was alpha 1, followed by alpha 3, alpha 5, alpha 2 and alpha v, with lesser amounts of alpha 4 and alpha 6. The beta 1 chain was expressed (on average) on the 40% of the chondrocytes regardless of the zone they were isolated from. Differential phenotypic analysis of the three zones showed that beta 1 integrins correlate inversely with the severity of the anatomic lesions and the cycle phase of the chondrocytes (the G0/G1 phase prevailed in the anatomically normal cartilage of the least damaged zone, and the S-phase in the most damaged zone).This study provides evidence of the existence of beta 1 integrins on the surface of chondrocytes from human OA cartilage, all of the alpha chains being represented, although in different percentages. Moreover, an inverse correlation was demonstrated between the severity of the anatomical changes found in the zones and the phenotypic/metabolic changes of the cells. These results, together with the well known inside-out signaling function of the adhesion molecules, highlight the key role of matrix interactions in the pathogenesis of the anatomic changes in OA.

The occurrence of certain antibacterial antibodies was studied in the sera of 22 healthy donors (HD) and 66 patients with different diseases. The cases investigated included 22 rheumatoid arthritis (RA), 22 non-arthritic-psoriasis (NAP), and 22 psoriatic arthritis (PA) patients. A complement fixation test was used with Yersinia enterocolitica 0:3 type (YEC), Yersinia pseudotuberculosis (YPT), Campylobacter jejuni (CJ), and Campylobacter fetus (CF) antigens; the detection of anti-Chlamydia trachomatis (CT) antibodies was carried out using an immunoperoxidase colorimetric slide test that allowed the detection of isotypes of specific antibodies. It was found that the synthesis of anti-CF, CJ, YEC, and YPT antibodies in NAP patients does not differ significantly from that of the HD group; on the contrary, the antibody levels were statistically higher in PA than in the other disease groups or in the healthy controls, although only anti-CF antibodies seemed to significantly differentiate (p = 0.000003) the PA group from the others. Anti-CT IgA antibody titers were found to be significantly higher in the PA as well as in the RA groups when compared with the controls, while the antibody levels in NAP patients showed no clear-cut difference with respect to those of either the arthritic patients or the healthy controls. By showing that anti-enterobacterial antibodies are increased in PA but not in NAP patients, our data furnish additional support to the thesis of a pathogenic role of bacterial infections in psoriatic arthritis.

To identify the time point of the greatest degree of improvement in daily living activities, pain and depression in patients with osteoarthritis (OA) of the knee during 6 months of treatment with NSAIDs, in order to define compliance and drop-out rate.107 patients were recruited into a multicentre, prospective, randomized, controlled trial comparing two treatments, piroxicam-beta-cyclodextrin (PBCD) and slow release diclofenac (DCL).The greatest improvement in quality of life occurred in both groups after 3 months, with a slight further gain observed by the end of treatment. The Stanford Health Assessment Questionnaire score improved (p0.05 vs baseline) at 3 and 6 months with PBCD and at 6 months with DCL. The Arthritis Impact Measurement Scale score improved (p0.05 vs baseline) after 6 months in both groups. Significant (p0.05 vs baseline) improvement in other psychological and pain scores were recorded in both groups after 3 and 6 months. Compliance with treatment at 3 months was 73% for PBCD and 72% for DCL, and was 60% in both groups at 6 months.The results of this study indicate that the optimal length of time for an NSAID trial in OA patients is 3 months, when assessment of daily living activities is considered as the main outcome criterion.

The etiology of rheumatoid arthritis (RA) is still unknown, and many uncertainties regarding its pathogenetic mechanisms persist. During the past decade, various hypotheses have been advanced, yet none of these has been able to explain the complexity of the disease. In light of the most recent research, a sub-division of the pathogenesis of RA, in four phases, has been proposed. The first phase is that of tissue damage, induced by unknown infective or traumatic factors with the liberation of possible arthrogenic antigens that are presented to the immune system. In the second phase the immune and inflammatory mechanisms should begin to function and, if they are effective, they should determine the resolution of the process; the failure of these mechanisms would create a further amplification of the immuno-inflammation response (the third phase). The fourth phase would then be a chronic inflammatory with progressive articular destruction, as well as anatomical and functional damage. This evolution, in response to common pathogenic agents, is dependent upon a particular hereditary genetic asset (not only the HLA system) that is able to control the production of citokines and also upon the neuroendocrine system. The final outcome of the process is, therefore, determinated by multiple interference between the inflammatory/immune system and other systems that also interact with it (the integrated pathogenetic hypothesis). This hypothesis reflects the complexity of the immune/inflammatory system that must be considered to be an acting part of an integrated network of diverse systems. A better knowledge of these interactions needed for the discovery of potential new therapies for RA.

To evaluate the cell surface expression of cell membrane-bound peptidases CD10 and CD26 on osteoarthritic (OA) chondrocytes, correlating it with the cell cycle phase and with the severity of OA lesions found in different load zones of the cartilage from human knees.Chondrocytes freshly isolated from three different load zones of cartilage, obtained from 10 OA patients undergoing surgical knee replacement, were analyzed for the expression of CD10 and CD26 and for their cell cycle phase by flow cytometry. Statistical analysis was carried out using the multifactorial analysis of the variance with the LSD (least square difference) range test. The Chi square test was used to compare the cell cycle phases.Analysis of the chondrocyte cell cycle showed a significantly high proportion of cells in the S-phase in the maximum load zone in comparison with the minimum load zone (p0.001); the percentage of resting cells (G0/G1 phase) was significantly higher in the minimum load zone than in the maximum load zone (p0.001). The expression of CD10 and CD26 on chondrocytes was significantly reduced in the maximum load zone of the cartilage and was directly related to the progressive worsening of osteoarthritic lesions.These data demonstrate, for the first time, that articular chondrocytes express on their surface CD10 and CD26 peptidases. Neprilysin 3.4.24.11 (CD10) and dipeptidyl peptidase IV 3.4.14.15 (CD26) have been shown to play a specific role in the control of growth and differentiation of many cell types by cleaving growth factors able to promote cellular proliferation. Our results indicate that CD10 and CD26 are down-regulated in the maximum load zone of the knee OA cartilage: this condition may allow the increase of local levels of growth factors causing chondrocyte activation. Furthermore, as CD26 mediates cell binding to fibronectin and collagen, its reduction in osteoarthritic cartilage may reflect a perturbation of chondrocyte interactions with the extracellular matrix.

We studied interleukin-10 (IL-10) levels in the blood and synovial fluid (SF) of 15 patients with RA and in the blood of 15 healthy donors (HD). RA IL-10 levels were significantly higher in SF than in blood (p = 0.001) and did not correlate with the disease activity nor with the therapy. RA patients showed significantly reduced blood IL-10 levels compared to the HD (p = 0.002), suggesting that IL-10 synthesis is depressed in RA. Since IL-10 has anti-inflammatory properties, reducing pro-inflammatory cytokine release by monocytes and down-modulating T cell function, its defect in RA may play a role in perpetuating RA synovitis.

The effects of human immunodeficiency virus type-1 (HIV-1) infection on rheumatoid arthritis (RA) are a matter of debate as there is no agreement on the influence of HIV-1 related immunodeficiency on this disease. We describe a patient with RA with symmetric joint erosions and positive rheumatoid factor (RF) who developed classic acquired immunodeficiency syndrome (AIDS) followed by left hemiplegia. RA improved with resolution of bony erosions and disappearance of RF, and reached complete clinical remission only in the paralytic limbs. Our observation suggests that, although essential, cell mediated immune response is not the sole mechanism involved in RA pathogenesis. Other factors such as the nervous system may play an important role.