The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis

Abstract

Osteoarthritis (OA) is the most common chronic disease of human joints. The basis of pathologic changes involves all the tissues forming the joint; already, at an early stage, it has the nature of inflammation with varying degrees of severity. An analysis of the complex relationships indicates that the processes taking place inside the joint are not merely a set that (seemingly) only includes catabolic effects. Apart from them, anti-inflammatory anabolic processes also occur continually. These phenomena are driven by various mediators, of which the key role is attributed to the interactions within the cytokine network. The most important group controlling the disease seems to be inflammatory cytokines, including IL-1 β , TNF α , IL-6, IL-15, IL-17, and IL-18. The second group with antagonistic effect is formed by cytokines known as anti-inflammatory cytokines such as IL-4, IL-10, and IL-13. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of OA with respect to inter- and intracellular signaling pathways is still under investigation. This paper summarizes the current state of knowledge. The cytokine network in OA is put in the context of cells involved in this degenerative joint disease. The possibilities for further implementation of new therapeutic strategies in OA are also pointed.

Figure 1

Schematic of a closed disease circle comprising the disease progression of osteoarthritis taking into account its causes and consequences.

Figure 2

IL-1β associated intracellular signaling pathways and downstream cellular targets and effects. IL-1R1: interleukin-1 receptor, type 1; IL-1R2: interleukin-1 receptor, type 2; MyD88: myeloid differentiation primary response gene (88); IRAK: interleukin-1 receptor-associated kinase; TRAF6: TNF receptor-associated factor 6; TAK1: also known as mitogen-activated protein kinase kinase kinase 7 (MAP3K7); TAB1: also known as mitogen-activated protein kinase kinase kinase 7 interacting protein 1 (MAP3K7IP1); TAB2: also known as mitogen-activated protein kinase kinase kinase 7 interacting protein 2 (MAP3K7IP2); p50, p65: subunits of proteins forming NF-κB; IκB: (inhibitor of κB) an endogenous complex of proteins inhibiting the activation of NF-κB; IKK1,2/NEMO: NF-κB inhibitor kinase 1,2 (IκB kinase 1,2)/NF-κB kinase inhibitor (NF-κB essential modulator); ERK: extracellular-signal-regulated kinase; JNK: c-Jun N-terminal kinase; p38: p38 mitogen-activated protein kinases; MAPK: mitogen-activated protein kinases; AP-1: activator protein 1.

Figure 3

TNFα associated intracellular signaling pathways and downstream cellular targets and effects. TNF-R1: tumor necrosis factor receptor superfamily member 1; TNF-R2: tumor necrosis factor receptor superfamily member 2; TRADD: tumor necrosis factor receptor type 1 associated death domain protein; FADD: Fas-associated protein with death domain; TRAF2: TNF receptor-associated factor 6; c-IAP1: also known as Baculoviral IAP repeat-containing protein 2 (BIRC2); c-IAP2: also known as Baculoviral IAP repeat-containing protein 3 (BIRC3); RIP1: receptor-interacting protein kinase 1; Ub: ubiquitin; TRAF3: TNF receptor-associated factor 3; TAK1: also known as mitogen-activated protein kinase kinase kinase 7 (MAP3K7); TAB1: also known as mitogen-activated protein kinase kinase kinase 7 interacting protein 1 (MAP3K7IP1); TAB2: also known as mitogen-activated protein kinase kinase kinase 7 interacting protein 2 (MAP3K7IP2); p50, p65: subunits of proteins forming NF-κB; IκB: (inhibitor of κB) an endogenous complex of proteins inhibiting the activation of NF-κB; IKK1,2/NEMO: NF-κB inhibitor kinase 1,2 (IκB kinase 1,2)/NF-κB kinase inhibitor (NF-κB essential modulator); ERK: extracellular-signal-regulated kinase; JNK: c-Jun N-terminal kinase; p38: p38 mitogen-activated protein kinases; MAPK: mitogen-activated protein kinases; AP-1: activator protein 1.

Figure 4

Schematic of the anti-inflammatory and chondroprotective effect of IL-4, IL-10, and IL-13 on articular cartilage during the course of OA.