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ABSTRACT
Aim of the study: To investigate the roles of endoplasmic reticulum (ER) transmembrane sensor inositol-requiring enzyme-1 (IRE1)α signaling in ER stress-induced chondrocyte apoptosis, and to determine the molecular mechanisms underlying chondroprotective activity of 5,7,3′,4′-tetramethoxyflavone (TMF) from Murraya exotica. Materials and methods: IRE1α was knocked down by siRNA transfection in chondrocytes, which were harvested from rats’ knee cartilages. Chondrocytes with IRE1α deficiency were administrated with tunicamycin (TM) and TMF. Chondrocyte apoptosis was quantified by flow cytometry and DAPI/TUNEL staining. Expression of mRNA and proteins was quantified by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western-blot, respectively. Results: IRE1α deficiency significantly increased the rate of TM-induced chondrocyte apoptosis, down-regulated the expression of pro-survival factors XBP1S and Bcl-2, and up-regulated pro-apoptotic factors CHOP, p-JNK, and caspase-3. TMF suppressed TM-induced chondrocyte apoptosis by activating the expression of IRE1α, which reversed the expression patterns of downstream pro-survival and pro-apoptotic factors due to IRE1α deficiency. Conclusion: The mechanism of TMF in protecting chondrocytes against ER stress-induced apoptosis might be associated with regulating the activity of ER sensor IRE1α and its downstream pathway.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
Funding
This study was financially supported by the National Science Foundation of China (81360277 and 81660371), the National Science Foundation of Jiangxi Province (20161BAB215219), Scientific Research Fund of Jiangxi Provincial Education Department (GJJ150959), and NIH P20GM104937.
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Funding
Notes on contributors
Longhuo Wu
All persons designated as authors qualify for authorship. Each author has contributed sufficiently to the work. LW and HL: conception and design, analysis and interpretation of the data, draft of the article; LL, DX, YGao, and YGuan: conception and design, analysis and interpretation of the data, critical revision of the article for important intellectual content. QC: analysis and interpretation of the data, critical revision, final approval of the article.
Haiqing Liu
All persons designated as authors qualify for authorship. Each author has contributed sufficiently to the work. LW and HL: conception and design, analysis and interpretation of the data, draft of the article; LL, DX, YGao, and YGuan: conception and design, analysis and interpretation of the data, critical revision of the article for important intellectual content. QC: analysis and interpretation of the data, critical revision, final approval of the article.
Linfu Li
All persons designated as authors qualify for authorship. Each author has contributed sufficiently to the work. LW and HL: conception and design, analysis and interpretation of the data, draft of the article; LL, DX, YGao, and YGuan: conception and design, analysis and interpretation of the data, critical revision of the article for important intellectual content. QC: analysis and interpretation of the data, critical revision, final approval of the article.
Daohua Xu
All persons designated as authors qualify for authorship. Each author has contributed sufficiently to the work. LW and HL: conception and design, analysis and interpretation of the data, draft of the article; LL, DX, YGao, and YGuan: conception and design, analysis and interpretation of the data, critical revision of the article for important intellectual content. QC: analysis and interpretation of the data, critical revision, final approval of the article.
Yun Gao
All persons designated as authors qualify for authorship. Each author has contributed sufficiently to the work. LW and HL: conception and design, analysis and interpretation of the data, draft of the article; LL, DX, YGao, and YGuan: conception and design, analysis and interpretation of the data, critical revision of the article for important intellectual content. QC: analysis and interpretation of the data, critical revision, final approval of the article.
Yingjie Guan
All persons designated as authors qualify for authorship. Each author has contributed sufficiently to the work. LW and HL: conception and design, analysis and interpretation of the data, draft of the article; LL, DX, YGao, and YGuan: conception and design, analysis and interpretation of the data, critical revision of the article for important intellectual content. QC: analysis and interpretation of the data, critical revision, final approval of the article.
Qian Chen
All persons designated as authors qualify for authorship. Each author has contributed sufficiently to the work. LW and HL: conception and design, analysis and interpretation of the data, draft of the article; LL, DX, YGao, and YGuan: conception and design, analysis and interpretation of the data, critical revision of the article for important intellectual content. QC: analysis and interpretation of the data, critical revision, final approval of the article.