In order to study the involvement of
mitogen-activated protein kinase p38 in
osteoarthritis, we investigated the effect of novel p38 inhibitor
R-130823 {2-(4-fluorophenyl)-4-(1-phenethyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(pyridin-4-yl)-1H-
pyrrole} on human chondrocytes and bovine cartilage. In human primary chondrocytes, the production of
matrix metalloproteinase-13 and -1 (MMP-13 and -1) and
prostaglandin E2 (
PGE2) was induced by
interleukin-1beta. Pretreatment with
R-130823 inhibited the release of MMP-13, MMP-1 and
PGE2 with IC50 values of 20, 230 and 3.9 nM, respectively. The inhibitory activity was also confirmed by a decrease in MMP-13 release from human
chondrosarcoma cell line SW1353 with an IC50 value of 17 nM.
Ribonuclease protection assay on human primary chondrocytes indicated that MMP-13 and MMP-1
mRNA levels almost reached the maximum 14 h after
IL-1 stimulation, while
cyclooxygenase-2 (COX-2)
mRNA quickly reached the maximum 4 h after the stimulation.
R-130823 down-regulated the steady-state levels of MMP-13 and MMP-1
mRNA with IC50 values of 4.2 and 79 nM, respectively. The COX-2
mRNA level was also suppressed with an IC50 value of 21 nM. In the explant culture of bovine nasal cartilage,
R-130823 suppressed the
collagen cleavage induced by
interleukin-1alpha and
oncostatin M, but not IL-1beta-mediated
glycosaminoglycan release. These results suggest that activated p38 accelerates cartilage breakdown by enhancing the expression of
MMPs responsible for
collagen cleavage, which thus implies chondroprotective effects of p38 inhibitors in
osteoarthritis.