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
Version of Record online: 3 JUN 2003
Copyright © 2003 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 48, Issue 6, pages 1582–1593, June 2003
How to Cite
Pelletier, J.-P., Fernandes, J. C., Brunet, J., Moldovan, F., Schrier, D., Flory, C. and Martel-Pelletier, J. (2003), 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. Arthritis & Rheumatism, 48: 1582–1593. doi: 10.1002/art.11014
- Issue online: 3 JUN 2003
- Version of Record online: 3 JUN 2003
- Manuscript Accepted: 13 FEB 2003
- Manuscript Received: 1 MAR 2002
- Pfizer Global Research & Development, Ann Arbor, Michigan
- Le Fonds de la Recherche en Santé du Québec (FRSQ)
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.
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.
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.
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.