Osteoarthritis: Inflammatory mediators Pisamai Laupattarakasem Dept. of Pharmacology Fact. Of Medicine Khon Kaen University 210848

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

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

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 and cartilage destruction

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

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.

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)

Other inflammatory agents: Nitric oxide (NO)

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

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

Flow chart for the therapy of osteoarthritis

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

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

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

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

IL-1 IL-1 (cont.) Recruits cells to site of inflammation, Stimulates production of IL-6 and TNF-a, Augments T-cell proliferation and B-cell activation, Induces hepatic production of acute phase proteins, Activates neutrophils to synthesis and release PGs, Increases binding of lymphocytes and monocytes to 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)

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

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

Management of OA: Pyramid approach ประชุมวิชาการ 48 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 IA steroids / HA Topical analgesics Surgery Prescription of NSAIDs OTC analgesics Acetaminophen Patient education PT & OT, Weight reduction Exercise, Assistive device Creamer P, Hochberg MC. Osteoarthritis (Seminar). Lancet 1997, 350:503-509. OA-cytokine_edited3