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Cytokines

Cytokines disrupt the balance of the anabolic and catabolic processes within the joint leading to progressive degeneration of the joint if left unchecked.

Cytokines can be pro-inflammatory or anti-inflammatory.  It is thought that the most important pro-inflammatory cytokines in the pathogenesis of OA are IL-1β and TNF-α.  Other pro-inflammatory cytokines thought to play a role in the pathogenesis of OA include IL-6, IL-17 and IL-18.

Anti-inflammatory cytokines thought to have a role in reducing the activity or production of the pro-inflammatory cytokines include IL-4, IL-10 and IL-13.

IL-1β

This is one of the key cytokines involved in the pathogenesis of OA.  It is synthesised in the joint by chondrocytes, osteoblasts, synovium and mononuclear cells and is increased in the joint in OA.  In the normal joint, the balance of IL-1 and its antagonist protein, IL-1Ra, is hypothesised to be important for the maintenance of homeostasis and prevention of OA.  In OA joints, there is increased expression of the IL-1 receptor on the surface of chondrocytes and fibroblast-like synoviocytes and a reduction in the production of IL-1Ra.  IL-1Ra is produced and secreted from synoviocytes and articular chondrocytes so any damage to these cells (as in OA) will lead to a reduction in the production of this molecule and hence a reduction in its antagonistic effects against IL-1.

IL-1 stimulates the production of:

  • Prostaglandin E2 – inhibits proteoglycan synthesis, induces collagen degradation
  • Nitrous Oxide – Causes apoptosis of cells and perpetuates the expression of pro-inflammatory cytokines
  • Cytokines – pro-inflammatory cytokines
  • Chemokines – mediate recruitment and traffic inflammatory cells
  • Adhesion molecules
  • Matrix metalloproteinases (MMPs) and other enzymes involved in cartilage degradation

TNF-α

Over production of TNF-α in OA by activated synoviocytes and articular chondrocytes leads to further matrix degradation in articular cartilage and drives the inflammatory process further.

It causes activation of the same group of intracellular signalling pathways that are involved when IL-1β is activated so has similar effects to IL-1β. 

IL-6

IL-6 production in the joint is usually in response to presence of IL-1 and TNF-α.  It is responsible for activating the immune system and and enhancing the inflammatory response.  In synergy with the other cytokines, it causes a decrease in the production of type II collagen and increases the production of MMPs and leads to resorption of subchondral bone by promoting osteoclast formation.

IL-17

IL-17 is produced from stimulated CD4+ T cells and mast cells and has the following effects within the joint:

  • Inhibit synthesis of proteoglycans by chondrocytes
  • Promotes production of MMPs
  • Influences the secretion of other cytokines that negatively affect cartilage (IL-1β, TNF-α, IL-6, NO, PGE2)
  • Causes excessive development of blood vessels within the synovial membrane and hence synovial hypertrophy

IL-18

Production of IL-18 in the joint is induced by IL-1β in articular chondrocytes and synovial cells

Actions of Il-18 include:

  • Increases concentration of MMPs
  • Inhibits production of type II collagen, proteoglycans and aggrecan
  • Increases the production of IL-6, inducible nitric oxide synthase (iNOS), PGE2, COX-2 and VEGF from chondrocytes and synovial cells.

References

  1. Martel-Pelletie J. Pathophysiology of osteoarthritis.  OsteoArthritis and Cartilage 2004; 12: (S31–S33)
  2. de Lange-Brokaar BJ, Ioan-Facsinay A, van Osch GJ, Zuurmond AM, Schoones J, Toes RE, Huizinga TW, Kloppenburg M. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review.  Osteoarthritis Cartilage 2012; 20(12): 1484–1499.
  3. Melchiorri C, Meliconi R, Frizziero L, Silvestri T, Pulsatelli L, Mazzetti I, Borzì RM, Uguccioni M, Facchini A. Enhanced and coordinated in vivo expression of inflammatory cytokines and nitric oxide synthase by chondrocytes from patients with osteoarthritis.  Arthritis & Rheumatology 1998; 41(12): 2165–2174.
  4. Massicotte F, Lajeunesse D, Benderdour M, Pelletier JP, Hilal G, Duval N, Martel-Pelletier J., Can altered production of interleukin-1β, interleukin-6, transforming growth factor-β and prostaglandin E2 by isolated human subchondral osteoblasts identity two subgroups of osteoarthritic patients.  Osteoarthritis and Cartilage 2002; 10(6): 491–500.
  5. Farahat MN, Yanni G, Poston R, Panayi GS.  Cytokine expression in synovial membranes of patients with rheumatoid arthritis and osteoarthritis.  Annals of the Rheumatic Diseases 1993; 52(12): 870–875.
  6. Szekanecz Z, Koch AE. Cell-cell interactions in synovitis. Endothelial cells and immune cell migration.  Arthritis Research 2000; 2(5): 368–373
  7. Arend WP, Gabay Physiologic role of interleukin-1 receptor antagonist. Arthritis Res. 2000; 2(4): 245–248.
  8. Fernandes JC, Martel-Pelletier J, Pelletier JP. The role of cytokines in osteoarthritis pathophysiology. Biorheology 2002; 39 (1-2):237-46
  9. Palmer G, Mezin F, Juge-Aubry CE, Plater-Zyberk C, Gabay C, Guerne PA. Interferon β stimulates interleukin 1 receptor antagonist production in human articular chondrocytes and synovial fibroblasts. Ann Rheum Dis. 2004; 63(1): 43-9
  10. Attur M, Al-Mussawir HE, Patel J, Kitay A, Dave M, Palmer G, Pillinger MH, Abramson SB. Prostaglandin E2 exerts catabolic effects in osteoarthritis cartilage: evidence for signaling via the EP4 receptor.  J Immunol. 2008; 181(7): 5082-8.
  11. Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum 2001; 44; 1237-1247
  12. Olee T, Hashimoto S, Quach J, Lotz M. IL-18 is produced by articular chondrocytes and induces proinflammatory catabolic responses.  J Immunol  1999; 162(2): 1096-1100.
  13. Udagawa N, Horwood NJ,Elliott J, Mackay A, Owens J, Okamura H, Kurimoto M, Chambers TJ, Martin TJ, Gillespie MT.  Interleukin-18 (interferon-gamma-inducing factor) is produced by osteoblasts and acts via granulocyte/macrophage colony-stimulating factor and not via interferon-gamma to inhibit osteoclast formation.  Journal of Experimental Medicine 1997; 185(6): 1005 – 1012
  14. Matsui K, Tsutsui H, Nakanishi K. Pathophysiological roles for IL-18 in inflammatory arthritis.  Expert Opin Ther Targets 2003; 7(6): 701-24