title: Thrombin promotes matrix metalloproteinase-13 expression through the PKCδ c-Src/EGFR/PI3K/Akt/AP-1 signaling pathway in human chondrocytes.
abstract: Thrombin is a key mediator of fibrin deposition, angiogenesis, and proinflammatory processes. 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 PKCδ, 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 PKCδ 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.
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan ; Department of Orthopaedic Surgery, China Medical University Beigang Hospital, Yunlin County, Taiwan ; School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Chun-Yin
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Department of Nursing, China Medical University Beigang Hospital, Yunlin County, Taiwan.
authors.forename: Hsiu-Jung
authors.initials: HJ
authors.lastname: Lin
authors.affiliation: School of Medicine, China Medical University, Taichung, Taiwan ; Department of Physical Medicine and Rehabilitation, China Medical University Beigang Hospital, Yunlin County, Taiwan.
authors.forename: Hsin-Shui
authors.initials: HS
authors.lastname: Chen
authors.affiliation: School of Medicine, China Medical University, Taichung, Taiwan ; Department of Obstetrics and Gynecology, China Medical University Beigang Hospital, Yunlin County, Taiwan.
authors.forename: Shi-Yann
authors.initials: SY
authors.lastname: Cheng
authors.affiliation: School of Medicine, China Medical University, Taichung, Taiwan ; Department of Orthopaedic Surgery, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Horng-Chaung
authors.initials: HC
authors.lastname: Hsu
authors.affiliation: School of Medicine, China Medical University, Taichung, Taiwan ; Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan ; Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D001172:Arthritis, Rheumatoid / Q000209:etiology; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D019902:Chondrocytes / Q000201:enzymology*; D066246:ErbB Receptors / Q000502:physiology; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000235:genetics*; D010003:Osteoarthritis / Q000209:etiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051745:Protein Kinase C-delta / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D044463:Receptor, PAR-1 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D066246:ErbB Receptors; D053509:Matrix Metalloproteinase 13; D019869:Phosphatidylinositol 3-Kinases; D051745:Protein Kinase C-delta; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D013917:Thrombin; D018808:Transcription Factor AP-1; D019061:src-Family Kinases; C512478:EGFR protein, human; C000631346:CSK protein, human; C497258:PRKCD protein, human; C507079:MMP13 protein, human