PFKFB 3 modulates glycolytic metabolism and alleviates endoplasmic reticulum stress in human osteoarthritis cartilage
Clinical and Experimental Pharmacology and Physiology(2016)
摘要
Summary Glycolytic disorder has been demonstrated to be a major cause of osteoarthritis ( OA ) and chondrocyte dysfunction. The present work aimed to investigate the expression and role of the glycolytic regulator 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase 3 ( PFKFB 3) in OA cartilage. It was found that PFKFB 3 expression was down‐regulated in human OA cartilage tissues and in tumour necrosis factor ( TNF )‐ α ‐ or interleukin ( IL )‐1 β ‐stimulated human chondrocytes. The glycolytic metabolism appeared as glucose utilization and adenosine triphosphate ( ATP ) generation, and lactate production was stunted in OA cartilage. However, the impaired glycolytic process in OA cartilage was improved by PFKFB 3 overexpression, which was confirmed in TNF ‐ α ‐ or IL ‐1 β ‐treated chondrocytes. Furthermore, the expressions of endoplasmic reticulum ( ER ) stress‐associated genes including PERK , ATF 3, IRE 1, phosphorylated eIF 2 α (p‐ eIF 2 α ) and MMP 13 were enhanced in OA cartilage explants, while they were decreased by Ad PFKFB 3 transfection. PFKFB 3 also modulated the expressions of PERK , ATF 3, IRE 1, p‐ eIF 2 α and MMP 13 in tunicamycin‐exposed chondrocytes. Additionally, PFKFB 3 improved the cell viability of OA cartilage explants and chondrocytes through the PI 3K/Akt/C/ EBP homologous protein ( CHOP ) signalling pathway. The transfection of Ad PFKFB 3 also significantly reduced caspase 3 activation and promoted aggrecan and type II collagen expressions in OA cartilage explants and chondrocytes. In all, this study characterizes a novel role of PFKFB 3 in glycolytic metabolism and ER stress of OA cartilage explants and chondrocytes. The study might provide a potential target for OA prevention or therapy.
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关键词
human osteoarthritis cartilage,endoplasmic reticulum stress,glycolytic metabolism
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