Cytokines and Chemokines Involved in Osteoarthritis Pathogenesis

Abstract

Osteoarthritis is a common cause of disability worldwide. Although commonly referred to as a disease of the joint cartilage, osteoarthritis affects all joint tissues equally. The pathogenesis of this degenerative process is not completely understood; however, a low-grade inflammation leading to an imbalance between anabolic and katabolic processes is a well-established factor. The complex network of cytokines regulating these processes and cell communication has a central role in the development and progression of osteoarthritis. Concentrations of both proinflammatory and anti-inflammatory cytokines were found to be altered depending on the osteoarthritis stage and activity. In this review, we analyzed individual cytokines involved in the immune processes with an emphasis on their function in osteoarthritis.

Keywords: biomarker; chemokines; cytokines; inflammation; osteoarthritis; pathogenesis.

Figure 1

Schematic representation of key inflammatory processes and factors in osteoarthritis pathogenesis. The disturbed balance of proinflammatory and anti-inflammatory cytokines (in favor of proinflammatory cytokines) is responsible for the secretion of enzymes and other inflammatory factors involved in the pathogenesis of osteoarthritis leading to morphological changes within the joint such as cartilage degeneration, osteophyte formation and other inflammatory changes such as synovitis. Chemokines also contribute to inflammatory processes, stimulating the chemotaxis of inflammatory cells that then further secrete proinflammatory cytokines, thus creating a vicious circle that poses a major challenge in treating and slowing the progression of osteoarthritis. IL—interleukin; CCL-CC—chemokine ligand; TNF-α—tumor necrosis factor α; MMPs—matrix metalloproteinases (MMPs); ADAMTS—a disintegrin-like and metalloproteinase with thrombospondin motif; COX-2—cyclooxygenase-2; PGE-2—prostaglandin E2; NO—nitric oxide.

Figure 2

Schematic representation of IL-1β function in osteoarthritis pathogenesis. By binding to its receptor (IL-1RI), IL-1β activates signaling pathways (NF-κB and MAPK) that, by raising the expression of enzymes (ADAMTS and MMPs), lead to catabolic reactions, i.e., proteoglycan degradation and collagen disruption. Furthermore, via the same signaling pathways, IL-1β inhibits type II collagen synthesis through SOX-9 suppression but also proteoglycan synthesis by increasing the synthesis of COX-2, PGE-2 and NO. In addition, IL-1β increases the expression of chemokines such as IL-8, CCL2 and CCL5, as well as the cytokines IL-6 and TNF-α, which attract inflammatory cells and cause synovial inflammation, respectively, resulting in the even greater production and secretion of IL-1β. IL-1β—interleukin 1β; IL-1RI—interleukin 1 receptor 1; MAPK—mitogen-activated protein kinase; ERK—extracellular signal-regulated kinases; JNK—c-Jun N-terminal kinases; NF-κB—nuclear factor kappa-light-chain-enhancer of activated B cells; MMPs—matrix metalloproteinases (MMPs); ADAMTS—a disintegrin-like and metalloproteinase with thrombospondin motif; COX-2—cyclooxygenase-2; PGE—prostaglandin E2; NO—nitric oxide; IL-8—interleukin 8; CCL2—chemokine ligand 2; CCL—chemokine ligand 5; SOX-9—SRY-Box Transcription Factor 9; IL-6—interleukin 6; TNF-α—tumor necrosis factor α.

Figure 3

Schematic representation of TNF-α function in osteoarthritis pathogenesis. TNF-α can bind to two receptors, TNRF-1 and TNRF-2. By binding to TNRF-1, TNF-α can induce two different signaling complexes. Complex 1 leads to the stimulation of cell survival and the expression of NF-κB, MAPK and AP-1, which results in proteoglycan degradation, collagen disruption and the inhibition of proteoglycan and collagen synthesis. On the other hand, the activation of complex 2 leads to a cascade of reactions, which include the formation of FADD and the activation of procaspase 8/10 and caspase 3, which consequently leads to cell apoptosis. Additionally, the binding of TNF-α to TNRF-2 activates NF-κB and JNK. In summation, TNF-α leads to degeneration of cartilage and other joint structures, thus contributing to the onset and progression of osteoarthritis. TNF-α—tumor necrosis factor α; TNRF-1—Tumor necrosis factor receptor 1; TNRF-2—Tumor necrosis factor receptor 2; TRADD—TNFR-1 associated death domain protein; RIP-1—receptor interacting protein-1; TRAF-2—TNF receptor-associated factor-2; MAPK—mitogen-activated protein kinase; ERK—extracellular signal-regulated kinases; JNK—c-Jun N-terminal kinases; NF-κB—nuclear factor kappa-light-chain-enhancer of activated B cells; AP-1—activator protein 1; FADD—Fas-associated death domain protein.

Figure 4

Schematic representation of IL-6 function in osteoarthritis pathogenesis. IL-6 acts by binding membrane-bound IL-6R or sIL-6R that associates with gp130. Gp130 initiates intracellular signaling that regulates the inflammation and expression of enzymes, collagen and proteoglycans. sIL-6R is produced by means of alternative splicing or the shedding of membrane-bound IL-6R. sgp130 can inhibit IL-6 signaling. Through classic and trans-signaling, IL-6 activates the PI3K, JAK/STAT and MAPK signaling pathways that regulate enzymes production (TIMP, MMPs and ADAMTS) and type II collagen and proteoglycan synthesis. Thus, IL-6 balances between anti-inflammatory and proinflammatory effects, but the latter predominates, ultimately leading to the progression of osteoarthritis. ADAM—a disintegrin and metalloproteinase; ADAMTS—a disintegrin-like and metalloproteinase with thrombospondin motifs; gp130—glycoprotein 130; IL-6—interleukin-6; MMP—matrix metalloproteinases; sgp130—soluble glycoprotein 130; sIL-6R—soluble IL-6 receptor; TIMP—tissue inhibitor of metalloproteinase; JAK/STAT—Janus kinase/signal transducers and activators of transcription; PI3K—phosphoinositide 3-kinases; MAPK—mitogen-activated protein kinase.