1. Hierarchical, imbalanced pro-inflammatory cytokine networks govern the pathogenesis of chronic arthropathies 
G. Livshits, A. Kalinkovich 
Osteoarthritis and Cartilage 
Volume 26, Issue 1, Pages 7-17 (January 2018)
DOI: /j.joca
Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

2. Fig. 1
Inflammation in chronic degenerative arthropathies. Joint inflammation is established by crosstalk between two main cell types: immune cells and joint resident cells (upper and middle rows in the diagram, respectively). Among the immune cells, T-cell subpopulations, such as Th1, Th9, Th17, and Th22 produce mainly pro-inflammatory cytokines, by suppressing the functional activity of the Th2, Treg, and Breg cells that secrete primarily anti-inflammatory cytokines. Dendritic cells (DCs), monocytes/macrophages, and neutrophils produce mostly pro-inflammatory cytokines and other soluble factors. In the joints, these factors activate resident cells (chondrocytes, fibroblasts, osteoclasts, and osteoblasts), triggering them to secrete various pro-inflammatory soluble factors as well as recruit immune cells into the joints, together building a strong and self-generating pro-inflammatory background. This microenvironment contributes to the development of the main joint inflammation-associated pathological events: cartilage damage, synovitis, pannus formation, SB erosion, ankylosis, and osteophyte formation. Although the mechanisms underlying joint inflammation are still evolving, it is believed that the products released from the cartilage matrix and/or the chondrocytes induce the release of soluble factors that deregulate chondrocyte function via paracrine and autocrine mechanisms. Secreted by chondrocytes, catabolic proteolytic enzymes degrade the cartilage matrix, releasing cartilage degradation products. The latter, along with the other pro-inflammatory soluble factors, induce the development of synovitis accompanied by the release of pro-inflammatory products by both infiltrating immune and local cells. These cells, in turn, provide feedback on chondrocytes, which exacerbate their functional deregulation and damage. In particular, the products of cartilage breakdown released into the SF are phagocytosed by synovial cells, amplifying the synovial inflammation. Moreover, the thickening of synovial tissue causes pannus formation, contributing to joint damage by producing excess fluid and proteolytic enzymes. Pannus contains high concentrations of RANKL-secreting osteoclasts that participate in SB erosion. Concomitantly, joint inflammation is accompanied by a down-regulation in the production of Wnt-signaling inhibitors, resulting in enhanced osteoblast proliferation and thus new bone formation, bone fusion (ankylosis), and the appearance of osteophytes (the low row of the diagram). All the aforementioned factors bind cognate receptors, consequently triggering various intracellular signal transduction events leading to the activation of an array of genes (not depicted). Taken together, these events result in degenerative arthropathies associated with pain and disability. Abbreviations: Th – T helper cell; TREG – T regulatory cell; BREG– B regulatory cells; IL-interleukin; IFN – interferon; TGF – transforming growth factor; ROS – reactive oxygen species; NO – nitrogen oxide; PGE2 – prostaglandin E2; NPY – neuropeptide Y.
Osteoarthritis and Cartilage  , 7-17DOI: ( /j.joca )
Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

3. Fig. 2
HIPICNs arising during the development of each of the depicted chronic arthropathies. The diagram shows HIPICNs, in which key pro-inflammatory cytokines and soluble factors (fragile nodes) interact with each other (in an auto/paracrine and systemic manner). This reciprocal interaction leads to amplification of the fragile nodes' overall functional activity by establishing pro-inflammatory detrimental vicious cycles, thus worsening the disease manifestations and outcome. The fragile nodes, which meet two main criteria – correlation with the disease severity and the ability to regulate the activity of other fragile nodes (Tables I and II), are depicted in colorless ellipses. The fragile nodes that meet an additional criterion – achieving the curative effect upon their selective inhibition (Table III), are depicted in yellow ellipses. Noteworthy is a remarkable similarity between the HIPICNs, whereas MIF, PED4, and TGFβ (in red ellipses) seem to be unique for RA-, PsA-, and OA-associated HIPICNs, respectively. For abbreviations, see the legend to Fig. 1.
Osteoarthritis and Cartilage  , 7-17DOI: ( /j.joca )
Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

4. Fig. 3
Common fragile nodes in the pathogenesis of different arthropathies. Among the HIPICN-associated fragile nodes meeting all three selection criteria (described in Fig. 2) are TNFα and IL-17, the IL-12/23 axis, the Wnt/RANKL and JAK/STAT signaling pathways; they are found to be common for RA, PsA, and AS (A). A wider range of common fragile nodes was found among those meeting the first two selection criteria (B). Some of them, namely, TNFα, IL-17, GM-CSF, the Wnt/RANKL and JAK/STAT signaling pathways, as well as IL-12/23 and the IL-20/22/24 axes (in blue ellipses) were found to be common for all five arthropathies. IL-9 (in green ellipses) merges four arthropathies. IL-1, IL-6, and IL-18 (in purple ellipses) combine RA, OA, and DDD, whereas IL-34 (in brown ellipse) merges RA and PsA. For abbreviations, see the legend to Fig. 1.
Osteoarthritis and Cartilage  , 7-17DOI: ( /j.joca )
Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions