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Osteoarthritis:Osteoarthritis:Inflammatory Inflammatory

mediatorsmediators

Pisamai Laupattarakasem

Dept. of Pharmacology

Fact. Of Medicine

Khon Kaen University

2

Loss of Loss of

HomeostaHomeosta

sis in sis in

cartilagecartilage

Catabolic:

Cartilage

breakdow

n• 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.

Etiopathology of osteoarthritis

3

A variety of cells se crete cytokines,

•macrophages,

• lymphocytes,

• fibroblasts, and

• endothelial cell

s,

The cytokines may be eith

er

- -pro inflammatory

cytokines

: - - - -1 6 8IL , IL , IL , and TNF

a or

- -anti inflammatory

cytokines

: - - -4 10 13IL , IL , IL

Cytokines

•Are extracellular peptide mediators

•Regulate cell growth, activity &

interaction

•Produced by leukocytes (in

inflammation)

& immune reaction

4

• The major targets for these cytokines in joint

inflammation are vessels , synovium , cartilage aaa , b

one

• The net result of cytokine activation

- Angiogenesis (n ew blood vessel formation) and

- I nflammatory cells infiltration to synovium

- synovitis and

- the subsequent bone and cartilage destruction

Cytokines (cont.)

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

Receptor type• - Type 1 IL 1 R • - Type 2 IL 1 R

• - - IL 1 receptor associated prot

ei n

- 1IL receptor (IL-1R)

• 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

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)

Tumor necrosis factor-α ( -TNF a)

8

Other inflammatory agents:

Nitric oxide (NO)

9

Inducible nitric oxide Inducible nitric oxide synthasesynthase

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

iNOS inhibitor

NO: OA cartilage degradation by • Down-regulating biosynthesis of aggrecan & collagen• Enhancing MMP activity • Inducing chondrocyte apoptosis.

10Schematic representation of two important arachidonic acid metabolic pathways. 5-LO, 5-lipoxygenase; COX,

cyclooxygenase;

Other inflammatory agents:

Arachidonate products

11

Flow chart for the therapy of osteoarthritis

12

TNF- inhibitors

• Soluble TNF receptor (sTNF R)

: Etanercept

• Monoclonal antibody (TNF MoAb)

: Infliximab,

Adalimumab

13

Recombination IL-1Ra

(rIL-1Ra): Anakinra

IL-1 agonis

t

IL-1 antagoni

st

IL-1antagonist

14

Soluble IL-1 receptor (sIL-1R)

IL-1 traping Neutralize IL-1 molecule

IL-1antagonist (cnot.)

15

• - 1IL family: • -1IL a , -1IL b: potent agonists •IL-1Ra ( - 1IL receptor antagonist,

competitive antagonist)

- Interleukin 1 (IL-1)

• - - -1 1IL a, IL b, and IL IRa are encoded by separat

e genes• Transcription is induced rapidly by various stimuli:

• B acterial cell wall components,

• C ytokines,

• Bradykinin, • I mmune stimuli, and

• I nflammatory mediators

16

• Recruits cells to site of inflammation,

•S timulates production of -a aaa aa a-a6 ,•A ugments -T cell proliferation and - B cell activation ,•I nduces hepatic production of acute phase proteins ,•A ctivates neutrophils to synthesis and release PGs,

•I ncreases binding of lymphocytes and monocytes to

ECs

•I nduces 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)

-IL1

I L- 1 (cont.)

17

• Stimulates production of - - -1 6 8IL , , and ;

• E - nhances PG dependent bone resorption;

• I nhibits collagen synthesis ;• I ncreases PGE2 and collagenase production

;• I ncreases plasminogen activity;

• I ncreases release of FGF ;• M odulates PMN function , such as phagocytos

is, adhesion to endothelium, release oxygen me

tabolites,

• D egrade cartilage

-TNF a (cont.)

18

Matrix metalloprotease (MMP)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

Management of OA: Pyramid approach

IA s

tero

ids

/ HA

IA s

tero

ids

/ HA

Topical analgesics

Topical analgesics

SurgerySurgery

Prescription Prescription

of NSAIDsof NSAIDs

OTC analgesicsOTC analgesics

AcetaminophenAcetaminophen

Patient educationPatient education

PT & OT, Weight reductionPT & OT, Weight reduction

Exercise, Assistive deviceExercise, Assistive device

Creamer P, Hochberg MC. Osteoarthritis (Seminar). Lancet 1997, 350:503-509.

EULAR= European League Against Rheumatism. 12 European countries: 18 Rheum, 3 Ortho, 2 EBG experts, knee OA, searched until 1998. ist report 2000