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Abstract White adipose tissue (WAT) is recognized to be a multifactorial organ. It has a major endocrine function secreting several hormones, most notably leptin and adiponectin, together with a diverse range of other protein signals and factors. These adipose-derived peptides have been termed collectively “adipokines” participate in functions correlated with energy homeostasis and metabolism. Moreover, adipokines represent a new family of compounds that can be currently considered as key players of the complex network of soluble mediators involved in the pathophysiology of rheumatic diseases. Adipokines include classic pro-inflammatory proteins such as TNF-α and IL-6, both secreted by adipocytes, but synthesized also by immune cells infiltrating WAT, such as macrophages and others as leptin, adiponectin, resistin, visfatin. These pro-inflammatory adipokines appear to significantly contribute to the so-called “low grade inflammation” of obese subjects, a condition associated with increased risk of cancer, type 2 diabetes, cardiovascular complications, autoimmune and inflammatory diseases including rheumatic diseases such as rheumatoid arthritis (RA), osteoarthritis (OA) and systemic lupus (SLE) . Summary & Recommendations 060 These adipokines include: 1. Leptin Leptin is a hormone with pleiotropic actions. In fact, in addition to regulation of food intake, it also affects a variety of other physiological functions, including fertility, bone metabolism, inflammation, infection, immune responses and others. Recent evidence demonstrates an involvement of leptin in promoting the pathogenesis of different autoimmune and rheumatic diseases such as rheumatoid arthritis, multiple sclerosis and SLE. Several authors have demonstrated dependence between the risk of aggressive course of RA and leptin levels. It is increasingly evident that this hormone plays a key role in the OA pathophysiology. Leptin expression is much higher in osteoarthritic human cartilage than in normal cartilage, and there exists a strong correlation of synovial fluid leptin levels with body mass index (BMI) in people with severe osteoarthritis. 2. Adiponectin . Adiponectin levels in RA patients are higher than in healthy subjects and multiple studies correlated these adiponectin elevated levels with severity of RA. Adiponectin is also implicated in OA pathogenesis. In chondrocytes this hormone is able to induce several pro-inflammatory mediators such as Summary & Recommendations 061 nitric oxide, IL-6, Monocyte chemoattractant protein-1(MCP-1), Matrix Metalloproteinases (MMP-3 and MMP-9) as well as IL-8, generating a proinflammatory environment at joint level. Plasma adiponectin levels were significantly higher in OA patients than in healthy subjects. High levels of adiponectin have been found in patients with SLE in comparison with healthy controls. It has been reported that plasma adiponectin levels are increased in patients with renal SLE compared to healthy controls and patients with non-renal SLE. During renal but not non-renal SLE flare, urine adiponectin levels increase significantly. For this reason, urine adiponectin may be a biomarker of renal SLE flare. 3. Resistin: Resistin is proposed as potential link between obesity and diabetes. It is secreted by adipose tissue but has been found also in macrophages, neutrophils, and other cell types. Actually, resistin has been found in the plasma and synovial fluid (SF) of RA patients and injection of this adipokine into mice joints induce an arthritis-like condition, with leukocyte infiltration of synovial tissues, hypertrophy of the synovial layer, and pannus formation .Studies have showed also that resistin induces and is induced by several proinflammatory cytokines, such as TNF-α or IL-6, in peripheral blood Summary & Recommendations 061 mononuclear cells, via Nuclear factor-Kappa B ( NF-κ B )pathway, indicating that resistin can increase its own activity by a positive feedback mechanism . The pro-inflammatory profile of resistin, together with its association with obesity suggest that this adipokine might be another potential mediator that links OA with inflammation and obesity. It was demonstrated that this adipokine is elevated in both serum and SF after traumatic joint injuries. Recombinant resistin stimulated proteoglycan degradation in mouse femoral head cultures and the induction of inflammatory cytokines and Prostaglandin E2 (PGE2) production. Moreover, it inhibits proteoglycan synthesis in human cartilage explants. In addition, resistin has a role as a marker of inflammation in other rheumatic diseases, such as SLE. In fact, Studies have demonstrated a positive correlation between serum resistin levels, inflammation, bone mineral density, and renal functions in patients with SLE. 4. Visfatin Visfatin may be considered another potential therapeutic target for RA with important pro-inflammatory and catabolic roles in RA pathogenesis, it has been reported that circulating visfatin is higher in patients with RA than in healthy controls, also enhanced visfatin levels are associated with augmented joint damage. Studies have showed that visfatin is a key mediator in inflammatory arthritis. Summary & Recommendations 061 The administration of a visfatin inhibitor to mice with collagen-induced arthritis reduced arthritis severity with similar effect to that produced by TNF-α inhibitor. At cartilage level, OA chondrocytes are able to produce visfatin and its expression is increased after IL-1β treatment. Visfatin administration, like IL-1β, enhances PGE2 release, also increases MMP-3 and MMP-13 synthesis and release. These data suggest that visfatin has a catabolic function in cartilage and may have an important role in the pathophysiology of OA. Also, it has been shown that, in SLE patients, visfatin levels were higher compared to healthy control. 5. Chemerin Chemerin and its receptor are mainly expressed, but not exclusively, in adipose tissue, for instance, dendritic cells and macrophages express chemerin receptor. Endothelial cells also express ChemR23 and it is up regulated by pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6. Moreover, chemerin exogenous challenge promotes in vitro angiogenesis by inducing cell proliferation, endothelial migration and capillary tube formation, critical steps in the development of angiogenesis Summary & Recommendations 061 Interestingly, chondrocytes express chemerin and its receptor and IL-1β is able to increase chemerin expression. Recombinant chemerin enhances the production of several pro-inflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-8), as well as different MMPs (MMP-1, MMP-2, MMP- 3, MMP 8 and MMP-13) in human articular chondrocytes. These factors play a role in the degradation of the extracellular matrix, by causing a breakdown of the collagen and aggrecan framework, which results in the irreversible destruction of the cartilage in OA and RA. Chemerin is natural ligand of Chem R 23, a receptor highly expressed by plasmacytoid DCs which infiltrate the kidney tubulointerstitial in patient with severe L.N leading to recruitment of leukocytes at renal level. Recommendations: Further experimental studies must be encouraged to elucidate the role of these Adipokines in different rheumatic diseases Also further studies are recommended to clarify the therapeutic approaches with drugs that target or enhance these adipokines in different rheumatic diseases. |