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Osteoarthritis: Inflammatory mediators

Osteoarthritis: Inflammatory mediators. Pisamai Laupattarakasem Dept. of Pharmacology Fact. Of Medicine Khon Kaen University. Anabolic: Cartilage synthesis TGF- β IGF-1 BMP. Catabolic : Cartilage breakdown IL-1 TNF- α IL-6 IL-18. Loss of Homeostasis in cartilage.

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Osteoarthritis: Inflammatory mediators

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  1. Osteoarthritis:Inflammatory mediators Pisamai Laupattarakasem Dept. of Pharmacology Fact. Of Medicine Khon Kaen University

  2. Anabolic: • Cartilage • synthesis • TGF-β • IGF-1 • BMP • Catabolic: • Cartilage breakdown • IL-1 • TNF-α • IL-6 • IL-18 Loss of Homeostasis in cartilage Etiopathology of osteoarthritis Cartilage destruction results from a failure of chondrocytes to maintain a homeostatic balance between matrix synthesis and degradation.

  3. Cytokines • Are extracellular peptide mediators • Regulate cell growth, activity & interaction • Produced by leukocytes (in inflammation) • & immune reaction The cytokines may be either - pro-inflammatorycytokines : IL-1, IL-6, IL-8, and TNF-aor - anti-inflammatorycytokines : IL-4, IL-10, IL-13 • A variety of cells secrete cytokines, • macrophages, • lymphocytes, • fibroblasts, and • endothelial cells,

  4. Cytokines (cont.) • The major targets for these cytokines in joint • inflammation are vessels, synovium, cartilage, and bone • The net result of cytokine activation • - Angiogenesis (new blood vessel formation) and • - Inflammatory cells infiltration to synovium • - synovitis and • -the subsequent bone andcartilage destruction

  5. Cytokines (cont.) Both IL-1 & TNF- Activate transcription factors nuclear factor kB (NFkB), which in turn increase transcription of a set of - pro-inflammatory gene, - additional molecules - IL-6 -8 - MMP - Prostanoids bone & cartilage destruction

  6. IL-1 receptor (IL-1R) • Receptor type • Type 1 IL-1 R • Type 2 IL-1 R • IL-1 receptor-associated protein • Both types of IL-1R can be shed from cell surface, • called IL-1 soluble receptors (IL-1sR), • decrease the responsiveness of target cells to IL-1.

  7. Tumor necrosis factor-α (TNF-a) • In OA, TNF-α appears to be a potentially • important mediator of matrix degradation and • a pivotal cytokine in synovial membrane inflammation. • TNF-α is synthesized as a pro-enzyme, • proteolytic cleavage by TNF-α converting enzyme (TACE) • This enzyme is also required for the shedding of TNF-R • TNF-α receptor (TNF-R), TNF-R55 and TNF-R75 • (named according to their molecular weight)

  8. Other inflammatory agents: Nitric oxide(NO)

  9. Inducible nitric oxide synthase • NO: OA cartilage degradation by • Down-regulating biosynthesis of • aggrecan & collagen • Enhancing MMP activity • Inducing chondrocyte apoptosis. • iNOS inhibitor Pelletier LP, Pelletier JM, Abramson SB. Osteoarthritis, an inflammatory disease: Potential implication for the selection of new therapeutic targets. Arthrtis rheum. 2001; 44 (6): 1237-47

  10. Other inflammatory agents: Arachidonate products Schematic representation of two important arachidonic acid metabolic pathways. 5-LO, 5-lipoxygenase; COX, cyclooxygenase;

  11. Flow chart for the therapy of osteoarthritis

  12. TNF- inhibitors • Soluble TNF receptor (sTNF R) • : Etanercept • Monoclonal antibody (TNF MoAb) • : Infliximab, • Adalimumab

  13. IL-1antagonist IL-1 agonist Recombination IL-1Ra (rIL-1Ra): Anakinra IL-1 antagonist

  14. IL-1antagonist (cnot.) Neutralize IL-1 molecule Soluble IL-1 receptor (sIL-1R) IL-1 traping

  15. Interleukin-1 (IL-1) • IL-1 family: • IL-1a, IL-1b:potent agonists • IL-1Ra(IL-1 receptor antagonist, • competitive antagonist) • IL-1a, IL-1b, and IL-IRa are encoded by separate genes • Transcription is induced rapidly by various stimuli: • Bacterial cell wall components, • Cytokines, • Bradykinin, • Immune stimuli, and • Inflammatory mediators

  16. IL-1 IL-1 (cont.) • Recruits cells to site of inflammation, • Stimulates production of IL-6 and TNF-a, • Augments T-cellproliferation and B-cell activation, • Induces hepatic production of acute phase proteins, • Activates neutrophils to synthesis and release PGs, • Increases binding of lymphocytes and monocytesto ECs • Induces endothelial cell proliferation and neovascularisation • Induces bone resorption, mediated through PGE2 • Causes cartilage destruction (IL-1 converts plasminogen to • plasmin, a neatral protease that causes cartilage destruction)

  17. TNF-a (cont.) • Stimulates production of IL-1, -6, and -8; • Enhances PG-dependent bone resorption; • Inhibits collagen synthesis; • Increases PGE2 and collagenase production; • Increases plasminogen activity; • Increases release of FGF; • Modulates PMN function, such as phagocytosis, adhesion to endothelium, release oxygen metabolites, • Degrade cartilage

  18. Matrix metalloprotease (MMP) Pelletier LP, Pelletier JM, Abramson SB. Osteoarthritis, an inflammatory disease: Potential implication for the selection of new therapeutic targets. Arthrtis rheum. 2001; 44 (6): 1237-47

  19. Surgery Prescription of NSAIDs OTC analgesics Acetaminophen Patient education PT & OT, Weight reduction Exercise, Assistive device IA steroids / HA Topical analgesics Management of OA: Pyramid approach EULAR= European League Against Rheumatism. 12 European countries: 18 Rheum, 3 Ortho, 2 EBG experts, knee OA, searched until 1998. ist report 2000 Creamer P, Hochberg MC. Osteoarthritis (Seminar). Lancet 1997, 350:503-509.

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