Thrombin Promotes Matrix Metalloproteinase-13 Expression through the PKCδ/c-Src/EGFR/PI3K/Akt/AP-1 Signaling Pathway in Human Chondrocytes
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...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2013-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2013/326041 |
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| author | Chun-Yin Huang Hsiu-Jung Lin Hsin-Shui Chen Shi-Yann Cheng Horng-Chaung Hsu Chih-Hsin Tang |
| author_facet | Chun-Yin Huang Hsiu-Jung Lin Hsin-Shui Chen Shi-Yann Cheng Horng-Chaung Hsu Chih-Hsin Tang |
| author_sort | Chun-Yin Huang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c1a556f8307d4b2d904f4ace744a4421 |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-c1a556f8307d4b2d904f4ace744a44212025-02-03T06:44:47ZengWileyMediators of Inflammation0962-93511466-18612013-01-01201310.1155/2013/326041326041Thrombin Promotes Matrix Metalloproteinase-13 Expression through the PKCδ/c-Src/EGFR/PI3K/Akt/AP-1 Signaling Pathway in Human ChondrocytesChun-Yin Huang0Hsiu-Jung Lin1Hsin-Shui Chen2Shi-Yann Cheng3Horng-Chaung Hsu4Chih-Hsin Tang5Graduate Institute of Clinical Medical Science, China Medical University, Taichung, TaiwanDepartment of Nursing, China Medical University Beigang Hospital, Yunlin County, TaiwanSchool of Medicine, China Medical University, Taichung, TaiwanSchool of Medicine, China Medical University, Taichung, TaiwanSchool of Medicine, China Medical University, Taichung, TaiwanSchool of Medicine, China Medical University, Taichung, TaiwanThrombin 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.http://dx.doi.org/10.1155/2013/326041 |
| spellingShingle | Chun-Yin Huang Hsiu-Jung Lin Hsin-Shui Chen Shi-Yann Cheng Horng-Chaung Hsu Chih-Hsin Tang Thrombin Promotes Matrix Metalloproteinase-13 Expression through the PKCδ/c-Src/EGFR/PI3K/Akt/AP-1 Signaling Pathway in Human Chondrocytes Mediators of Inflammation |
| title | Thrombin Promotes Matrix Metalloproteinase-13 Expression through the PKCδ/c-Src/EGFR/PI3K/Akt/AP-1 Signaling Pathway in Human Chondrocytes |
| title_full | Thrombin Promotes Matrix Metalloproteinase-13 Expression through the PKCδ/c-Src/EGFR/PI3K/Akt/AP-1 Signaling Pathway in Human Chondrocytes |
| title_fullStr | Thrombin Promotes Matrix Metalloproteinase-13 Expression through the PKCδ/c-Src/EGFR/PI3K/Akt/AP-1 Signaling Pathway in Human Chondrocytes |
| title_full_unstemmed | Thrombin Promotes Matrix Metalloproteinase-13 Expression through the PKCδ/c-Src/EGFR/PI3K/Akt/AP-1 Signaling Pathway in Human Chondrocytes |
| title_short | Thrombin Promotes Matrix Metalloproteinase-13 Expression through the PKCδ/c-Src/EGFR/PI3K/Akt/AP-1 Signaling Pathway in Human Chondrocytes |
| title_sort | thrombin promotes matrix metalloproteinase 13 expression through the pkcδ c src egfr pi3k akt ap 1 signaling pathway in human chondrocytes |
| url | http://dx.doi.org/10.1155/2013/326041 |
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