Investigation of the effect and mechanism of resistin in osteoarthritis

Autor: Chen, Wei-Cheng, 陳暐錚
Rok vydání: 2019
Druh dokumentu: 學位論文 ; thesis
Popis: 107
Osteoarthritis (OA) is the most common form of arthritis and affects a large portion of aged population worldwide. The pathogenesis of osteoarthritis (OA) is still not fully understood due to the complex interaction of genetic, biochemical, and mechanical factors involved in this disease. Resistin is a dimeric protein that may be involved in the pathogenesis of multiple inflammatory diseases including osteoarthritis. Have been reported that MCP-1 play a critical role in the pathogenesis of OA by regulating monocyte migration and infiltration. However, the effects of resistin on monocyte chemoattractant protein-1 (MCP-1) expression in osteoarthritis synovial fibroblasts (OASFs) remain unknown. In this study, resistin was found to activate the phosphatidylinositol-3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) signaling pathways, while PI3K, Akt, and mTOR inhibitors or small interfering RNAs diminished resistin-induced MCP-1 expression and monocyte migration. In addition, resistin was shown to stimulate MCP-1-mediated monocyte migration by suppressing miR-33a and miR-33b via the PI3K, Akt and mTOR signaling pathways. These results provide new insights into the mechanisms of resistin and may have therapeutic implications for patients with OA. In addition, much evidence has revealed that interleukin-1β (IL-1β) and Tumor Necrosis Factor-α (TNFa) are the main proinflammatory cytokine involved in the pathophysiology of OA. In OA chondrocytes, levels of IL-1β and TNFa are markedly increased, which not only suppresses the synthesis of the extracellular matrix (ECM), but also stimulates the release of catabolic proteases such as matrix metalloproteinase (MMPs). However, the effects of resistin on IL-1β and TNFa responses in OA remain unknown. Here, our preliminary data showed that pretreatment of cells with resistin increased IL-1β and TNFa expression in OA cells. Our data showed that resistin induced MEK, and ERK phosphorylation. In addition, resistin-induced IL-1β and TNFa expression were antagonized by MEK, and ERK inhibitors. Therefore resistin enhances IL-1β and TNFa expression involved in MEK and ERK signaling pathways, whereas miR-149 expression is negatively affected by resistin via the MEK and ERK pathways. Our results illustrate the clinical significance of degenerative OA and explore the understanding of the signaling mechanisms of the synovial fibroblasts, which are expected to lead to new therapeutic strategies to reduce inflammatory responses. Osteoarthritis (OA) is the most common form of arthritis and affects a large portion of aged population worldwide. The pathogenesis of osteoarthritis (OA) is still not fully understood due to the complex interaction of genetic, biochemical, and mechanical factors involved in this disease. Resistin is a dimeric protein that may be involved in the pathogenesis of multiple inflammatory diseases including osteoarthritis. Have been reported that MCP-1 play a critical role in the pathogenesis of OA by regulating monocyte migration and infiltration. However, the effects of resistin on monocyte chemoattractant protein-1 (MCP-1) expression in osteoarthritis synovial fibroblasts (OASFs) remain unknown. In this study, resistin was found to activate the phosphatidylinositol-3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) signaling pathways, while PI3K, Akt, and mTOR inhibitors or small interfering RNAs diminished resistin-induced MCP-1 expression and monocyte migration. In addition, resistin was shown to stimulate MCP-1-mediated monocyte migration by suppressing miR-33a and miR-33b via the PI3K, Akt and mTOR signaling pathways. These results provide new insights into the mechanisms of resistin and may have therapeutic implications for patients with OA. In addition, much evidence has revealed that interleukin-1β (IL-1β) and Tumor Necrosis Factor-α (TNFa) are the main proinflammatory cytokine involved in the pathophysiology of OA. In OA chondrocytes, levels of IL-1β and TNFa are markedly increased, which not only suppresses the synthesis of the extracellular matrix (ECM), but also stimulates the release of catabolic proteases such as matrix metalloproteinase (MMPs). However, the effects of resistin on IL-1β and TNFa responses in OA remain unknown. Here, our preliminary data showed that pretreatment of cells with resistin increased IL-1β and TNFa expression in OA cells. Our data showed that resistin induced MEK, and ERK phosphorylation. In addition, resistin-induced IL-1β and TNFa expression were antagonized by MEK, and ERK inhibitors. Therefore resistin enhances IL-1β and TNFa expression involved in MEK and ERK signaling pathways, whereas miR-149 expression is negatively affected by resistin via the MEK and ERK pathways. Our results illustrate the clinical significance of degenerative OA and explore the understanding of the signaling mechanisms of the synovial fibroblasts, which are expected to lead to new therapeutic strategies to reduce inflammatory responses.
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