Hepatocyte growth factor induction of collagenase 3 production in human osteoarthritic cartilage - Involvement of the stress-activated protein kinase/c-Jun N-terminal kinase pathway and a sensitive p38 mitogen-activated protein kinase inhibitor cascade

Objective. Osteoarthritis (OA) involves both a decreased reparative process and an increased degradative phenomenon. Several cytokines and growth fact ors are known to facilitate the repair of articular cartilage defects, The hepatocyte growth factor (HGF) present in OA cartilage is suggested to be i nvolved in the cartilage repair process as well as in matrix remodeling and chondrocyte migration, leading to partial reconstruction of articular cart ilage. Since cell migration is often correlated with metalloprotease activi ty, the effect of HGF on collagenase 3 production was studied because of it s possible implication in OA cartilage remodeling. Methods. We examined HGF-stimulated collagenase 3 production in human OA ch ondrocytes by Western and Northern blotting, Furthermore, we explored the i ntracellular signaling pathways through which HGF induced collagenase 3 pro duction. Results, This study showed that HGF stimulated collagenase 3 production in human OA chondrocytes at the transcriptional level, and this induction was mediated by activation of the stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) pathway, but not the p38 mitogen-activated protein kinase (MAPK). The p44/42 MAPKs were also phosphorylated and the use of the ir specific inhibitor (PD 98059) did not affect HGF-induced collagenase 3 p roduction in OA chondrocytes. Induced collagenase 3 production via the SAPK /JNK pathway was mediated, at least in part, by the TRE site in the promote r, and in the activator protein 1 complex, c-Jun, JunD, and Fra-1 were acti vated. Surprisingly, further experiments revealed that the specific p38 MAP K inhibitor SE 202190 also inhibited collagenase 3 production early in the HGF-induced process. The 50% inhibitory concentration was as low as 50 nM, which is unlikely to be related to p38 MAPK inhibition (which is usually in the muM range), suggesting the involvement of another kinase sensitive to SE 202190. Conclusion. This is the first study to show that HGF has the ability to ind uce both the expression and synthesis of collagenase 3 in OA chondrocytes. The effect is mediated by kinase cascades involving SAPK/JNK and another, u nidentified kinase. This study provides novel information implicating a rol e for HGF in the pathophysiology of OA through its effect on the production of collagenase 3, which is an enzyme that is possibly involved in OA carti lage remodeling.