P173 THE EFFECTS OF INTRA-ARTICULAR INJECTION OF P38 MAPK INHIBITOR ON MATRIX METALLOPROTEINASE IN CARTILAGE OF EXPERIMENTAL OSTEOARTHRITIS MODEL

Abstract

Purpose: The primary aim of this study was to investigate, using an experimental rat model of osteoarthritis(OA), the effect of a selective p38 mitogen activated protein kinase inhibitor,SB203580, on the development of structural changes.Additional aims were to assess the effects of the inhibitor on levels of matrixmetalloproteinase 3 (MMP-3) and MMP-13(collagenase 3) in OA cartilage and to explore the relation between the MMP-3,13 expression and the severity of OA. Methods: OA was induced in 40 SD rats by anterior cruciate ligament transection (ACLT).After surgical, rats with OA were randomly divided into A_D groups: Rats of group A received 0.1 ml intra-articular injection of SB203580 at high concentration of 100um/L. Each treatment started immediately after surgery, once a week;those in group B were treated under the same condition using SB203580 with low concentration of 10um/L and those in group C received 0.1ml of intra-articular 0.9% Sodium Chloride injection,animals of group D were not injected as controls after ACLT. The animals were killed 8 weeks after surgery. Macroscopicand histologic studies were performed on the cartilage. The levels of MMP-3,13 in OA cartilage chondrocytes were evaluated by immunohistochemistry and western-blotting. Results: All ACLT knees demonstrated osteoarthritic changes. Cartilage degradation in the control group was significantly more severe than that in the experimental group both on the macroscopic grading scale and on Mankin’s grading scale(P <0.05). Immunohistochemical study showed that in the experimental group MMP-3,13 was predominantly expressed in the superficial and upper intermediate layers of cartilage, and the amount of MMP-3,13 in the experimental group was also lower than that in control group(P <0.05). In western-blotting the amount of MMP3,13 was reduced by the treatment of the inhibitor. The protein levels of MMP-3 and MMP-13 in cartilage of inhibitor injection groups were significantly lower than those of Sodium Chloride group and untreated group. There was no significant difference in MMP-3 and MMP-13 expression between the different concentration inhibitor injection groups. No significant difference in MMP-3 and MMP-13 expression in cartilage was found between Sodium Chloride group and control group. Conclusions: This study demonstrates that, in vivo,SB203580, a selective inhibitor of p38MAPK, can partially decrease the development of some of the structural changes in the early phases of experimental OA and significantly reduces the severity of cartilage degradation. This effect was associated with a reduction in the level of MMP-3,13 in OA cartilage, which probably explains the action of the drug and thus may be a potential drug for the treatment of OA.