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

2. 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.

3. 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

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 and cartilage 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):

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

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

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-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)

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):

19. 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 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:
OA-cytokine_edited3