Thrombin Promotes Matrix Metalloproteinase-13 Expression through the PKCδ/c-Src/EGFR/PI3K/Akt/AP-1 Signaling Pathway in Human Chondrocytes

Author:

Huang Chun-Yin123,Lin Hsiu-Jung4,Chen Hsin-Shui35,Cheng Shi-Yann36,Hsu Horng-Chaung37,Tang Chih-Hsin389

Affiliation:

1. Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan

2. Department of Orthopaedic Surgery, China Medical University Beigang Hospital, Yunlin County, Taiwan

3. School of Medicine, China Medical University, Taichung, Taiwan

4. Department of Nursing, China Medical University Beigang Hospital, Yunlin County, Taiwan

5. Department of Physical Medicine and Rehabilitation, China Medical University Beigang Hospital, Yunlin County, Taiwan

6. Department of Obstetrics and Gynecology, China Medical University Beigang Hospital, Yunlin County, Taiwan

7. Department of Orthopaedic Surgery, China Medical University Hospital, Taichung, Taiwan

8. Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan

9. Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan

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 PKCδand 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.

Funder

National Science Council

Publisher

Hindawi Limited

Subject

Cell Biology,Immunology

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