title: PFKFB3 modulates glycolytic metabolism and alleviates endoplasmic reticulum stress in human osteoarthritis cartilage.
abstract: 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 (PFKFB3) in OA cartilage. It was found that PFKFB3 expression was down-regulated in human OA cartilage tissues and in tumour necrosis factor (TNF)-α- or interleukin (IL)-1β-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 PFKFB3 overexpression, which was confirmed in TNF-α- or IL-1β-treated chondrocytes. Furthermore, the expressions of endoplasmic reticulum (ER) stress-associated genes including PERK, ATF3, IRE1, phosphorylated eIF2α (p-eIF2α) and MMP13 were enhanced in OA cartilage explants, while they were decreased by AdPFKFB3 transfection. PFKFB3 also modulated the expressions of PERK, ATF3, IRE1, p-eIF2α and MMP13 in tunicamycin-exposed chondrocytes. Additionally, PFKFB3 improved the cell viability of OA cartilage explants and chondrocytes through the PI3K/Akt/C/EBP homologous protein (CHOP) signalling pathway. The transfection of AdPFKFB3 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 PFKFB3 in glycolytic metabolism and ER stress of OA cartilage explants and chondrocytes. The study might provide a potential target for OA prevention or therapy.
authors.affiliation: Department of Paediatric Orthopaedics, Honghui Hospital, Xi'an Jiaotong University, Xian, China.
authors.forename: Jining
authors.initials: J
authors.lastname: Qu
authors.affiliation: Department of Trauma, Honghui Hospital, Xi'an Jiaotong University, Xian, China.
authors.forename: Daigang
authors.initials: D
authors.lastname: Lu
authors.affiliation: Department of Paediatric Orthopaedics, Honghui Hospital, Xi'an Jiaotong University, Xian, China.|Department of Emergency, Honghui Hospital, Xi'an Jiaotong University, Xian, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Paediatric Orthopaedics, Honghui Hospital, Xi'an Jiaotong University, Xian, China.
authors.forename: Wusheng
authors.initials: W
authors.lastname: Miao
authors.affiliation: Department of Paediatric Orthopaedics, Honghui Hospital, Xi'an Jiaotong University, Xian, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Paediatric Orthopaedics, Honghui Hospital, Xi'an Jiaotong University, Xian, China.
authors.forename: Meifen
authors.initials: M
authors.lastname: Zhou
mesh_terms: D000328:Adult; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006019:Glycolysis; D006801:Humans; D008875:Middle Aged; D010003:Osteoarthritis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D025481:Phosphofructokinase-2 / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: C497249:DDIT3 protein, human; D051742:Transcription Factor CHOP; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3
keywords: CHOP; PFKFB3; endoplasmic reticulum stress; glycolysis; osteoarthritis