Adipose Tissue in Rheumatoid Arthritis: Comparison
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Rheumatoid arthritis (RA) is a systemic autoimmune disease that primarily affects the joints. Organokines can produce beneficial or harmful effects in this condition. Among RA patients, organokines have been associated with increased inflammation and cartilage degradation due to augmented cytokines and metalloproteinases production, respectively. The adipose tissue (AT) is involved in the endocrine regulation of the body’s homeostasis and not only in the energetic homeostasis. Adipocytes drive the production and secretion of endocrine molecules (adipokines), which can control lipid metabolism and insulin sensitivity, inflammation, fibrogenesis, immunological responses, liver fat deposition, and fibrogenesis. Adipokines were the first organokines related to the pathophysiology of RA, collaborating in the inflammatory response on the affected joints. Adipokines also play a relevant role in developing extra-articular inflammation-dependent manifestations of RA. In musculoskeletal disorders such as RA, adipokines were described as modulators of bones, synovial membranes, and cartilages activities. Additionally, higher levels of adipokines are encountered in both serum and synovial fluid in patients with RA than in those who are healthy.

  • Rheumatoid arthritis
  • adipose tissue
  • Adiponectin

1. Introduction

Rheumatoid arthritis (RA) is a chronic systemic and autoimmune disease that affects approximately 1% of the world’s population. Being characterized mainly by persistent articular inflammation, this condition affects the synovial membranes of the joints, leading to joint destruction, loss of functions, and osteoarticular disabilities. In the disease’s progression, bone and cartilage are destroyed, which brings deformities to the patients [1][2][3]. Although RA is prevalent worldwide, its incidence is higher among women when compared to men, with an incident ratio of about two or three women to one man, respectively.
The physiopathology of RA is still not fully understood. However, many cells have been implicated in its development. In RA, the joint damage is driven principally due to the activity of proliferative synovial tissue fibroblasts, which are accompanied by neutrophils, monocytes, and T and B lymphocytes trafficking into the articular synovium. These cells are mainly pro-inflammatory, secreting many pro-inflammatory cytokines into the articular cavities [1][2].
Besides inflammation, oxidative stress (OS) also plays an essential role in the pathogenesis and progress of RA impairments. The excessive production of free radicals causes the oxidation of many different molecules in the human body, including articular. These events seem to be positive and extensively associated with augmented inflammation and accelerated joint destruction [3][4]. Due to its complex systemic definition, RA can also be associated with extra-articular manifestations, such as cardiologic, hepatic, pulmonary, digestive, ocular, dermatological, and neurological [5].
In the molecular context, organokines (myokines, osteokines, hepatokines, and adipokines) have been increasingly investigated in the pathophysiology of many diseases, such as insulin resistance (IR), dementia, non-alcoholic fatty liver disease, and cardiovascular affections. They are mainly adipokines, myokines, hepatokines, and osteokines, which are produced by adipose tissue, skeletal muscle, liver, and bones, respectively. Organokines can have beneficial or harmful effects on the human body besides performing crosstalk among different organs. Acting through endocrine, autocrine, or paracrine pathways can evidence inflammatory and oxidative stimuli [6][7]. Recently, organokines have shown an important role in the rheumatological field, inclusive of RA biomarkers.
In RA disease, organokines have been shown to promote inflammation or augment cartilage degradation by increasing pro-inflammatory cytokine production and metalloproteinases (MMPs) secretion, respectively. In turn, these molecules can associate with more serious radiographic damage among RA patients and immune dysregulation, combining T-cells differentiation and angiogenesis stimuli. Among many other actions, organokines are associated with the RA disease progression, and the roles of these molecules in RA and their possible cross-talks must become clearer [8][9][10].

2. Adiponectin

Adiponectin is composed of 244 amino acids produced and secreted by adipocytes to produce effects, mainly in the liver and skeletal muscle cells. Two adipokine receptors were found to respond to adiponectin, that is, adipoR1 and adipoR2. In health and against CVD, adiponectin exerts anti-inflammatory actions in obesity, atherosclerosis, type 2 diabetes mellitus, and metabolic syndrome, principally when in high concentrations. In muscles, the main effects of adiponectin are the increase in free fatty acid oxidation and glucose uptake. In the liver, adiponectin reduces gluconeogenesis. Paradoxically, in RA pathogenesis, the roles of this adipokine seem to be different [11][12][13].
Adiponectin in RA is pro-inflammatory to the joints, principally due to its ability to stimulate the production and secretion of inflammatory mediators. In RA patients, plasma and synovial adiponectin levels correlate positively with radiographic damage. Increased adiponectin concentrations promote inflammation by the production of TNF-α, IL-6, and IL-8. Interestingly, the erythrocyte sedimentation rate (ESR), CRP, and RF increase adiponectin concentrations in active disease RA patients. Many researchers also suggest that baseline levels of adiponectin can predict the gravity of RA’s radiographic progression. In synovial fibroblasts, adiponectin induces the production of prostaglandin E2, MMPs 1 and 13, IL-6, and IL-8. In human chondrocytes, adiponectin seems to stimulate the production of nitric oxide, IL-6, IL-8, MMP-3, MMP-9, and the monocyte chemoattractant protein (MCP) 1. Adiponectin also shows effects on promoting differentiation of T cells from naïve to Th17 (T helper 17 cells) state, which contributes to synovial inflammation and increases bone erosion in RA patients, causing major deformations. Lymphocytes and endothelial cells respond locally in joints to the presence of adiponectin, causing inflammation. Synovial macrophages and synovial fibroblasts also are stimulated by adiponectin in the lining and sub-lining layers of joints, leading to more inflammation and angiogenesis (fibroblasts start to produce the vascular endothelial growth factor—VEGF). In angiogenesis, adiponectin-derived production of VEGF by synovium fibroblasts leads to endothelial progenitor cell formation and migration [8][9][10][11][14][15].

3. Leptin

Leptin is the main adipokine secreted by adipocytes and has a role in stimulating chronic, low-grade inflammation in obese individuals, increasing IL-6 and TNF-α production. In addition to its unhealthy inflammatory role, leptin is also related to decreasing the body’s sensitivity to adiponectin in obesity. Among other actions, this adipokine is implicated in regulations of basal metabolism, insulin secretion, reproduction, and bone mass. Its production is controlled by food intake, sex hormones, energy status, and inflammatory mediators. Leptin can also modulate both the innate and adaptive immune systems by activating proliferation and activation of macrophages and monocytes, regulating the cytotoxicity of natural killer cells, modulating neutrophils chemotaxis, and controlling T CD4, Th1 (T helper 1), and Th2 (T helper 2) cells’ phenotypes [16][17][18][19].
This adipokine was associated with obesity and CVD, increased disease course velocity, and increased disease activity and duration among RA patients. For these reasons, higher leptin levels were correlated with increased joint erosion. Leptin also modulates inflammation through JAK2/STAT3, NF-kB, and activating protein-1 (AP-1) pathways, maintaining positive correlations mainly with IL-17 in plasma and IL-6 and IL-8 in the synovial fluid of RA patients. Adhesion molecule production was also stimulated by leptin in human chondrocytes through JAK2, PI3K, and MAPK signaling pathways, which potentializes leukocyte invasion in inflamed joints [17][18][20][21][22].

4. Visfatin (Pre-B-Cell Colony-Enhancing Factor—PBEF)

Visfatin/PBEF is an adipokine initially described as an early B-cell development cytokine and is secreted mainly by visceral adipocytes. Recently, visfatin/PBEF gained attention due to its relevant roles in neurological and oncological disorders a key inflammation regulator in these conditions. Visfatin/PBEF has also been related to the emergence of musculoskeletal diseases, such as RA. Although visfatin/PBEF can be secreted by other non-AT organs such as skeletal muscles, liver, lungs, kidneys, and bone marrow, its secretion is higher in adipocytes. It is considered only an adipokine. In RA patients, visfatin/PBEF can also be secreted by activated joint synovium, cartilage, and mononuclear cells, increasing joint inflammation. Visfatin/PBEF can also work as an enzyme. In summary, the main enzymatical roles of visfatin/PBEF depend on NAD+ vital cellular processes, which gives visfatin/PBEF nicotinamide phosphoribosyl transferase (NAMPT) effects. In metabolic diseases, visfatin/PBEF correlates with augmented IR and pancreatic β-cells dysfunction [10][23][24].
Pathologically, visfatin/PBEF in RA exerts many actions. This adipokine was related to up-regulating inflammation through signal transducers and activators of transcription 3 (STAT-3)-dependent IL-6 trans-signaling and poly(I-C)-mediated TLR-3 (TLR-3) pathways in activated RA synovium fibroblasts. In these fibroblasts, visfatin/PBEF activates the NF-kB, which leads to inflammation. Other inflammatory mediators are also produced through visfatin/PBEF stimulation in RA, such as IL-6, MMP-3, MMP-10, MMP-12, and MMP-19, which only augment an aggressive phenotype in RA synovium fibroblasts. Visfatin/PBEF also activates chondrocytes to produce prostaglandin E2 and MMP-3. These visfatin/PBEF effects on fibroblasts and chondrocytes up-regulate joint damage and destruction. In turn, visfatin/PBEF correlates intimately with RA disease activity and progression and its radiographic progression over four years of the disease. In RA, visfatin/PBEF also up-regulates the total number of circulating B cells, which can contribute to autoimmunity. In this field, CD14+ monocytes are stimulated by visfatin/PBEF to produce IL-6, TNF-α, and IL-1β. Many studies reported that visfatin/PBEF also mediates chemoattraction of immunological cells to the synovia by stimulating elevated expressions of adhesion molecules, such as vascular-cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and intercellular adhesion molecule 2 (ICAM-2), and chemokines, such as of CXC and CC clusters. VCAM-1, VCAM-2, and ICAM-2 promote attachment and migration of RA-activated synovium fibroblasts to cartilage via the CXC/CC enhanced cell motility. Attraction and extravasation of leukocytes are also promoted by visfatin/PBEF by stimulation of interstitial angiogenesis. This adipokine demonstrated pro-angiogenic effects by expressing extracellular signal-regulated kinase 1/2 (ERK 1/2) and fibroblast growth factor 2 (FGF-2) in endothelium-activated cells. The actions of visfatin/PBEF in RA are summarized in contributing to inflammation, matrix degradation, and angiogenesis [10][25][26][27][28].

5. Omentin

Omentin is a glycoprotein adipokine first described in patients with bowel disease although it is found in the plasma of clinically healthy individuals. The visceral AT is the one that most secretes omentin. Besides other effects, omentin is described as cardioprotective and anti-atherogenic, mainly due to its vasculoprotective and vasodilatory actions. This adipokine is considered anti-inflammatory, modulating activation and proliferation of macrophages to the M2 phenotype. It is also negatively associated with metabolic syndrome. Low serum levels of omentin are associated with obesity, and high levels are associated with insulin sensitivity improvement. In RA patients, hypo-omentinemia is related to chronic inflammation. Added to that, low levels are encountered in the synovial fluid of RA participants. A positive and direct relationship was described between overweight and increased risk of RA development in individuals with positive autoantibodies for this disease. Omentin is also inversely correlated with MMP-3 production among RA individuals. A role of omentin against RA is that this adipokine can successfully decrease activation of Janus kinase 2/STAT3 (JAK-2/STAT3) pathways, which reduces inflammation and decreases MMP (metalloproteinase) production. To date, the roles that omentin exerts in rheumatic diseases are still unclear, and further researches are necessary to truly evaluate this adipokine in RA pathophysiology and progression [24][29][30][31][32].

6. Resistin

Among obese patients, resistin is associated with the occurrence of IR and the development of CVD. The resistin actions can be related to its pro-inflammatory properties in obesity, mainly driving the production of TNF-α and IL-6 cytokines. In RA patients’ serum and synovial fluid, higher levels are associated with increased chemokine production by fibroblast-like synoviocytes, which contributes positively to the RA pathophysiology. Additionally, studies have demonstrated that resistin could have a pro-inflammatory role among RA patients, increasing mainly inflammatory biomarkers, such as CRP. Some studies also demonstrated that resistin can augment angiogenesis among endothelial progenitor cells due to VEGF increased production, which only facilitates RA pathophysiology in increasing possibilities to leukocytes’ migration into the articular synovial spaces of individuals with RA. Indeed, the association between resistin levels and leukocyte count, as well as IL-6 levels in the synovial fluid of RA patients, was found to be positive [10][14][33][34][35][36].

7. Chemerin

Chemerin is a pro-inflammatory adipokine with endocrine, paracrine, and autocrine effects and is involved in the pathophysiology of many different metabolic disorders, such as metabolic syndrome, IR, and obesity. This adipokine is highly expressed in the white AT (WAT), liver, and lung tissues. However, chemerin can act as an anti-inflammatory under specific conditions. In contrast with other organokines that generally influence tissues, chemerin receptors are primarily expressed among immune cells [37][38].
In RA, chemerin induces FLS to produce metalloproteinases such as MMP-3, promoting cartilage damage and articular degradation. Chemerin is also associated with RA disease activity and severity, which helps predict disease progression. Among RA patients, chemerin promotes inflammation by inducing many pro-inflammatory cytokines, such as IL-6 and IL-1β. Besides MMP-3, other degradation-related molecules can be produced by chondrocytes stimulated by chemerin among RA patients, such as the C-C motif ligand 2 (CCL2). Combining inflammation and angiogenesis in RA pathophysiology, chemerin also stimulates motility and migration of immune and fibroblast cells to the joints, augmenting cartilage degradation [29][30][39][40][41][42].

8. Vaspin

Visceral AT-derived serpin protease inhibitor (vaspin) is an adipokine that belongs to the serine protease inhibitors family. Although its secretion occurs mainly by the visceral and subcutaneous AT, vaspin is expressed among other organs, such as the liver, stomach, skin, and pancreas. Vaspin biological activities are related mainly to glucose metabolism, appetite control, and lipid profile control, protecting against diabetogenic gene expression and reducing local inflammation in AT. Vaspin also enhances insulin secretion and β-cells protection in the pancreas and promotes vascular function. In the blood vessels, it reduces pro-inflammatory stimuli and decreases the presence of vascular adhesion molecules. In turn, it promotes macrophage phenotype modification from M1 to M2 and decreases ROS production. The appetite is associated with a decrease in neuropeptide Y secretion and increases in energy expenditure. In the liver, it augments insulin half-life and promotes augmented insulin signaling [43][44][45].
In RA patients, vaspin seems to be elevated compared to controls. Due to this presence, this adipokine correlates extensively and positively with the inflammatory response of these individuals and is also associated with muscle inflammation among RA individuals. Along with other data, previous research conducted with RA symptomatic and non-symptomatic patients concluded that the serum levels of vaspin might be associated with RA symptomatology, reflecting disease activity and symptoms progression [29][30][46][47].

9. Apelin

Apelin is an adipokine that intimately correlates with the cardiovascular system, helping control cardiac function (contractility) and blood pressure. Additionally, this molecule also plays an essential role in diabetes and obesity, being considered mainly in the progression of these two comorbidities. Produced principally by the AT, apelin was encountered in the brain, lungs, bloodstream, and kidneys. More recently, this adipokine correlated positively with RA pathophysiology [30][48][49].
Among RA individuals, apelin levels are decreased. This adipokine in RA and other rheumatic diseases increases the endothelial progenitor cell angiogenesis via inhibition of the miR-525-5p/angiopoietin-1 pathway. Additionally, apelin correlated positively with MMP-2 but inversely with MMP-9 among RA patients. In turn, in vitro studies using chondrocytes showed that apelin could promote the production of many metalloproteinase types, such as MMP-1, MMP-3, and MMP-9, added to inflammatory cytokines, such as IL-1β. However, the most important role of apelin in RA individuals seems to be related to the prediction of RA patients’ cardiovascular risk, insofar as apelin, along with the inflammation of RA, can be used to predict atherosclerosis development and atheroma plaque stability in RA patients.

10. Fibroblast Growth Factor 21 (FGF-21)

FGF-21 is an organokine released mainly by AT and regulates glucose and lipid metabolism. In RA individuals, increased levels of FGF-21 are found, principally in seropositive patients. In many cases, FGF-21 can also stimulate bone resorption when in contact with muscles in response to insulin signaling. However, in RA, the roles of FGF-21 are mainly anti-inflammatory, decreasing macrophage mediate inflammation (suppressing Nrf2 and NF-kB) and pro-inflammatory cytokines secretion. FGF-21 decreases TNF-α, IL-1β, IL-6, IL-17, IL-2, MMP-3, and IFN-γ (interferon-gamma) levels and, on the other hand, increases IL-10. In RA, FGF-21 is also considered an ameliorator of the disease activity due to antioxidant and immunological actions. FGF-21 can inhibit oxidation due to disbalances between pro-oxidative/anti-oxidative enzymes. In turn, FGF-21 can decrease the activity of both cellular and humoral immune responses in individuals affected by RA. To maintain joint integrity, FGF-21 blocks the production of cathepsin K and metalloproteinases, especially the MMP-3 [16][50][51][52][53][54].

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