الفهرس 
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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) .
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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
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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
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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.
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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
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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.