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.

Abstract

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.

CONCLUSION:

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.

• Authors: Jean-Pierre Pelletier, Julio C Fernandes, Julie Brunet, Florina Moldovan, Denis Schrier, Craig Flory, Johanne Martel-Pelletier
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 48 Issue 6 Pg. 1582-93 (Jun 2003) ISSN: 0004-3591 [Print] United States
• PMID: 12794826 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Fluorobenzenes
• PD 198306
• Protein-Tyrosine Kinases
• Protein Serine-Threonine Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• Mitogen-Activated Protein Kinase Kinases
• Collagenases
• collagenase 1
• Matrix Metalloproteinase 1

Topics

• Animals
• Cartilage, Articular (drug effects, metabolism, pathology)
• Chondrocytes (drug effects, metabolism, pathology)
• Collagenases (metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Fluorobenzenes (pharmacology)
• Hindlimb (surgery)
• Immunohistochemistry
• Longitudinal Ligaments (surgery)
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• Male
• Matrix Metalloproteinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• Mitogen-Activated Protein Kinases (metabolism)
• Osteoarthritis, Knee (drug therapy, enzymology, pathology)
• Phosphorylation
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Rabbits
• Synovial Membrane (drug effects, pathology)
• Synovitis (drug therapy, pathology)