Moderation of iodoacetate-induced experimental osteoarthritis in rats by matrix metalloproteinase inhibitors.
OBJECTIVE
To determine the effect of matrix metalloproteinase (MMP) inhibitors in mono-iodoacetate-induced arthritis in rats.


METHODS
The ability of compounds to inhibit MMPs in vitro was assessed kinetically using a quenched fluorescent substrate. Rats were injected with iodoacetate intraarticularly in one knee joint and damage to the tibial plateau was evaluated from digitized images captured using an image analyser and by histology. Collagenase and gelatinase activity in cartilage from iodoacetate injected knees were evaluated using(3)H-rat type I collagen and gelatin zymography, respectively.


RESULTS
Collagenase and gelatinase activity significantly increased in the knee cartilage of rats injected with iodoacetate with peak activity by day 7. Three MMP inhibitors were examined for their efficacy in the rat iodoacetate-induced arthritis model. Significant (P< 0.05) inhibition of cartilage damage was observed in animals treated orally with 35 mg/kg b.i.d. of the three different MMP inhibitors. Inhibition of cartilage damage by the MMP inhibitors ranged from 36-42%.


CONCLUSIONS
MMP inhibitors are partially protective against cartilage and subchondral bone damage induced by iodoacetate. These results support an important role for MMPs in mediating the joint damage in this model of arthritis.
Janusz
M J
MJ
Procter & Gamble Pharmaceuticals, Inc., 8700 Mason-Montgomery Rd, Mason, Ohio 45040-9462, USA. janusz.mj@pg.com
Hookfin
E B
EB
Heitmeyer
S A
SA
Woessner
J F
JF
Freemont
A J
AJ
Hoyland
J A
JA
Brown
K K
KK
Hsieh
L C
LC
Almstead
N G
NG
De
B
B
Natchus
M G
MG
Pikul
S
S
Taiwo
Y O
YO
D000818:Animals; D017364:Collagenases / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D018093:Gelatinases / Q000378:metabolism; D007091:Image Processing, Computer-Assisted / Q000379:methods; D007270:Injections, Intra-Articular; D007461:Iodoacetates / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D010003:Osteoarthritis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D007461:Iodoacetates; D061965:Matrix Metalloproteinase Inhibitors; D017364:Collagenases; D018093:Gelatinases