title: ATF6 upregulates XBP1S and inhibits ER stress-mediated apoptosis in osteoarthritis cartilage.
abstract: As we previously reported, transcription factor XBP1S enhances BMP2-induced chondrocyte differentiation and acts as a positive mediator of chondrocyte hypertrophy. The purpose of this study was to determine (1) whether XBP1S influences ER stress-mediated apoptosis in osteoarthritis (OA); (2) whether ATF6 regulates IRE1/XBP1 signal pathway in OA cartilage; (3) what are the associated molecules affecting apoptosis in osteoarthritis and the molecular events underlying this process. Herein, we examined and found that ER stress-associated molecules were activated in OA patients, specifically XBP1S splice and expression were increased markedly by TNF-α and IL-1β treatments. Transcription factor ATF6 can specifically bind to the promoter of XBP1 gene and enhance the expression of XBP1S spliced by IRE1α in osteoarthritis cartilage. Furthermore, siXBP1S can enhance ER stress-mediated apoptosis and main matrix degradation in osteoarthritis. Whereas AdXBP1S can inhibit ER stress-mediated apoptosis and TNFα induced nitrite production in OA cartilage. In a word, our observations demonstrate the importance of XBP1S in osteoarthritis. ATF6 and IRE1α can regulate endogenous XBP1S gene expression synergistically in OA cartilage. More significantly, XBP1S was a negative regulator of apoptosis in osteoarthritis by affecting caspase 3, caspase 9, caspase 12, p-JNK1, and CHOP.
authors.affiliation: Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China. Electronic address: guo.fengjin@gmail.com.
authors.forename: Feng-Jin
authors.initials: FJ
authors.lastname: Guo
authors.affiliation: Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Zhangyuan
authors.initials: Z
authors.lastname: Xiong
authors.affiliation: Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Health Statistics, College of Public Health and Management, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Mengliang
authors.initials: M
authors.lastname: Ye
authors.affiliation: Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Han
authors.affiliation: Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
mesh_terms: D051702:Activating Transcription Factor 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism / Q000503:physiopathology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000071717:X-Box Binding Protein 1
chemical_list: D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D053583:Interleukin-1beta; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases
keywords: ATF6; Apoptosis; BMP2; Cartilage; ER; ER stress response element; ERSE; Endoplasmic reticulum stress; IRE1; OA; Osteoarthritis; PERK; PKR-like ER resistant kinase; UPR; X-box binding protein 1 spliced form; XBP1S; activating transcription factor 6; bone morphogenetic protein 2; endoplasmic reticulum; inositol requiring enzyme 1; osteoarthritis; unfolded protein response