In vivo selective inhibition of mitogen-activated protein kinase kinase 1/2 in rabbit experimental osteoarthritis is associated with a reduction in the development of structural changes.
OBJECTIVE
The primary aim of this study was to investigate, using an experimental rabbit model of osteoarthritis (OA), the effect of a selective mitogen-activated protein kinase kinase 1/2 (MEK-1/2) inhibitor, PD 198306, on the development of structural changes. Additional aims were to assess the effects of the inhibitor on levels of phosphorylated extracellular signal-regulated kinase 1/2 (phospho-ERK-1/2) and matrix metalloproteinase 1 (MMP-1; collagenase 1) in OA chondrocytes.


METHODS
After surgical sectioning of the anterior cruciate ligament of the right knee joint, rabbits with OA were separated into 3 experimental groups: oral treatment with placebo or with PD 198306 at a therapeutic concentration of 10 mg/kg/day or 30 mg/kg/day. Each treatment started immediately after surgery. The animals were killed 8 weeks after surgery. Macroscopic and histologic studies were performed on the cartilage and synovial membrane. The levels of phospho-ERK-1/2 and MMP-1 in OA cartilage chondrocytes were evaluated by immunohistochemistry. Normal, untreated rabbits were used as controls.


RESULTS
OA rabbits treated with the highest dosage of MEK-1/2 inhibitor showed decreases in the surface area (size) of cartilage macroscopic lesions (P < 0.002) and in osteophyte width on the lateral condyles (P = 0.05). Histologically, the severity of synovial inflammation (villous hyperplasia) was also reduced (P < 0.02). In cartilage from placebo-treated OA rabbits, a significantly higher percentage of chondrocytes in the superficial layer stained positive for phospho-ERK-1/2 and MMP-1 compared with normal controls. Rabbits treated with the highest dosage of PD 198306 demonstrated a significant and dose-dependent reduction in the level of phospho-ERK-1/2 and a lower level of MMP-1.


CONCLUSIONS
This study demonstrates that, in vivo, PD 198306, a selective inhibitor of MEK-1/2, can partially decrease the development of some of the structural changes in experimental OA. This effect was associated with a reduction in the level of phospho-ERK-1/2 in OA chondrocytes, which probably explains the action of the drug.
Pelletier
Jean-Pierre
JP
Hôpital Notre-Dame, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada. dr@jppelletier.ca
Fernandes
Julio C
JC
Brunet
Julie
J
Moldovan
Florina
F
Schrier
Denis
D
Flory
Craig
C
Martel-Pelletier
Johanne
J
D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017364:Collagenases / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005464:Fluorobenzenes / Q000494:pharmacology*; D006614:Hindlimb / Q000601:surgery; D007150:Immunohistochemistry; D017846:Longitudinal Ligaments / Q000601:surgery; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011817:Rabbits; D013583:Synovial Membrane / Q000187:drug effects / Q000473:pathology; D013585:Synovitis / Q000188:drug therapy / Q000473:pathology
D004791:Enzyme Inhibitors; D005464:Fluorobenzenes; C475178:PD 198306; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases; D017364:Collagenases; C417249:collagenase 1; D020781:Matrix Metalloproteinase 1