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Abnormalities in these processes are primary features of rheumatoid arthritis and osteoarthritis. Matrix metalloproteinase-13 (MMP-13) may contribute to the breakdown of articular cartilage during arthritis. However, the role of thrombin in MMP-13 production in chondrocytes is unknown. In this study, we investigated the intracellular signaling pathways involved in thrombin-induced MMP-13 expression in human chondrocytes. We found that stimulation with thrombin led to increased secretion of MMP-13 in cultured human chondrocytes. Further, this thrombin-induced MMP-13 production was reduced after transfection with siRNAs against protease activated receptors 1 and 3 (PAR1 and PAR3), but not with PAR4 siRNA. Treatment with specific inhibitors for PKC<jats:italic>\u03b4<\/jats:italic>, c-Src, EGFR, PI3K, Akt, or AP-1 or with the corresponding siRNAs against these signaling proteins also abolished the thrombin-mediated increase in MMP-13 production in chondrocytes. Our results provide evidence that thrombin acts through the PAR1\/PAR3 receptors and activates PKC<jats:italic>\u03b4<\/jats:italic>and c-Src, resulting in EGFR transactivation and activation of PI3K, Akt, and finally AP-1 on the MMP-13 promoter, thereby contributing to cartilage destruction during arthritis.<\/jats:p>","DOI":"10.1155\/2013\/326041","type":"journal-article","created":{"date-parts":[[2013,12,9]],"date-time":"2013-12-09T21:01:30Z","timestamp":1386622890000},"page":"1-12","source":"Crossref","is-referenced-by-count":39,"title":["Thrombin Promotes Matrix Metalloproteinase-13 Expression through the PKC<i>\u03b4<\/i>\/c-Src\/EGFR\/PI3K\/Akt\/AP-1 Signaling Pathway in Human Chondrocytes"],"prefix":"10.1155","volume":"2013","author":[{"given":"Chun-Yin","family":"Huang","sequence":"first","affiliation":[{"name":"Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan"},{"name":"Department of Orthopaedic Surgery, China Medical University 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