Organokines in Rheumatoid Arthritis: A Critical Review

Abstract

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. This study aimed to perform a review to investigate the role of adipokines, osteokines, myokines, and hepatokines on RA progression. PubMed, Embase, Google Scholar, and Cochrane were searched, and 18 studies were selected, comprising more than 17,000 RA patients. Changes in the pattern of organokines secretion were identified, and these could directly or indirectly contribute to aggravating RA, promoting articular alterations, and predicting the disease activity. In addition, organokines have been implicated in higher radiographic damage, immune dysregulation, and angiogenesis. These can also act as RA potent regulators of cells proliferation, differentiation, and apoptosis, controlling osteoclasts, chondrocytes, and fibroblasts as well as immune cells chemotaxis to RA sites. Although much is already known, much more is still unknown, principally about the roles of organokines in the occurrence of RA extra-articular manifestations.

Keywords: adipokines; crosstalk; hepatokines; inflammation; myokines; organokines; osteokines; oxidative stress; rheumatoid arthritis; rheumatology.

Figure 1

Flow diagram showing the literature search and study selection criteria. Analysis of the literature and writing of the manuscript were performed following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines [12].

Figure 2

Representative scheme showing the main organokines and their balance in controlling the health and progression of RA disease. In general, organokines interact with different cells from different tissues involved in the pathophysiology of RA and, through these reactions, can lead these cells to develop inflammatory patterns, for example, or also produce and secrete metalloproteinases. BMPs, bone morphogenetic proteins; FGF-21, fibroblast growth factor 21; FSTL1, follistatin-like 1; FGL1, fibrinogen-like protein 1; ANGPTL-4, angiopoietin-like 4; LECT2, leukocyte cell-derived chemotaxin-2; SHBG, sex hormone-binding globulin.

Figure 3

In bones, osteopontin is produced by specific induction, and in the synovium of joints affected by RA, it causes inflammation, production of metalloproteinases, and immune dysregulation. Mainly affecting macrophages, osteoclasts, lymphocytes, and fibroblasts, osteopontin is essential for the disease progression and the formation of bone erosions. ↑, increase; ↓, decrease; TNF-α, tumor necrosis factor alfa; IL-6, interleukin 6; Th17, T helper 17; CD4, cluster of differentiation 4; Th1, T helper 1; Th2, T helper 2.

Figure 4

Adiponectin’s actions promote RA disease occurrence and progression. Although the major role of adiponectin in the body remains metabolically, adiponectin can also be associated with the development of rheumatological diseases. This adipokine promotes inflammation, immune dysregulation, and angiogenesis among RA patients, insofar as it can promote joint destruction. Particularly, angiogenesis can increase leukocyte influx to the interior of the joints. ↑, increase; ↓, decrease; IL-6, interleukin 6; IL-8, interleukin 8; MMP-1, metalloproteinase 1; MMP-13, metalloproteinase 13; Th17, T helper 17; NO, nitric oxide; TNF-α, tumor necrosis factor alfa; MMP-9, metalloproteinase 9; MCP-1, monocyte chemoattractant protein; VEGF, vascular endothelial growth factor.

Figure 5

Particularly, the pro-inflammatory cytokines liberated by affected RA joints can lead the liver to decrease the production of its proteins, such as the sex-hormone-binding globulin (SHBG). While the levels of SHBG decrease, the levels of free androgens increase. These androgens can prospect anti-inflammatory and immunoinhibitory actions in RA pathophysiology, protecting the body against this disease and its harmful effects. The activities of the free androgens are mainly driven against macrophages’ inflammation and T-cell and B-cell dysregulation. ↑, increase; ↓, decrease; TNF-α, tumor necrosis factor alfa; IL-1β, interleukin 1 beta; TNF-αR, tumor necrosis factor alfa receptor; IL-1βR, interleukin 1 beta receptor; IkBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; MEK, mitogen activated protein kinase; JNK, N-terminal kinase; NF-kB, nuclear factor-kappa b; c-JUN, c-Jun N-terminal kinase; PPARγ2, Peroxisome proliferator-activated receptor gamma 2; HNF-4α, hepatocyte nuclear factor-4 alpha; IL-6, interleukin 6; IL-8, interleukin 8; IL-10, interleukin 10; NO, nitric oxide; TLR4, toll-like receptor 4; Th1, T helper 1.

Figure 6

Organokines with simultaneous classifications that are involved in the pathophysiology and progression of RA disease. By acting together and combined, organokines can potentialize health or disease and lead to augmented disease activity. ↑, increase; ↓, decrease; Φ, inhibition; RA, rheumatoid arthritis; RANKL, receptor activator of nuclear factor kappa-Β ligand; NF-kB, nuclear factor kappa b; MCSF, macrophage colony-stimulating factor; MMP-1, metalloproteinase 1; MMP-3, metalloproteinase 3; MMP-13, metalloproteinase 13; IFN-γ, interferon gamma; MMP. Metalloproteinases; CVD, cardiovascular diseases; FSTL1, follistatin-like 1; FGL1, fibrinogen-like protein 1; ANGPTL-4, angiopoietin-like 4; LCN2, lipocalin 2.