title: XBP1S associates with RUNX2 and regulates chondrocyte hypertrophy.
abstract: BMP2 (bone morphogenetic protein 2) is known to activate unfolded protein response signaling molecules, including XBP1S and ATF6. However, the influence on XBP1S and ATF6 in BMP2-induced chondrocyte differentiation has not yet been elucidated. In this study, we demonstrate that BMP2 mediates mild endoplasmic reticulum stress-activated ATF6 and directly regulates XBP1S splicing in the course of chondrogenesis. XBP1S is differentially expressed during BMP2-stimulated chondrocyte differentiation and exhibits prominent expression in growth plate chondrocytes. This expression is probably due to the activation of the XBP1 gene by ATF6 and splicing by IRE1a. ATF6 directly binds to the 5'-flanking regulatory region of the XBP1 gene at its consensus binding elements. Overexpression of XBP1S accelerates chondrocyte hypertrophy, as revealed by enhanced expression of type II collagen, type X collagen, and RUNX2; however, knockdown of XBP1S via the RNAi approach abolishes hypertrophic chondrocyte differentiation. In addition, XBP1S associates with RUNX2 and enhances RUNX2-induced chondrocyte hypertrophy. Altered expression of XBP1S in chondrocyte hypertrophy was accompanied by altered levels of IHH (Indian hedgehog) and PTHrP (parathyroid hormone-related peptide). Collectively, XBP1S may be a novel regulator of hypertrophic chondrocyte differentiation by 1) acting as a cofactor of RUNX2 and 2) affecting IHH/PTHrP signaling.
authors.affiliation: Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Yanna
authors.initials: Y
authors.lastname: Liu
authors.forename: Jinghua
authors.initials: J
authors.lastname: Zhou
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhao
authors.forename: Xiangzhu
authors.initials: X
authors.lastname: Li
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
authors.forename: Chuanju
authors.initials: C
authors.lastname: Liu
authors.forename: Feng-Jin
authors.initials: FJ
authors.lastname: Guo
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D006132:Growth Plate / Q000378:metabolism / Q000473:pathology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006984:Hypertrophy; D051379:Mice; D008807:Mice, Inbred BALB C; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D024043:Collagen Type II; D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D044162:Parathyroid Hormone-Related Protein; D000071701:Regulatory Factor X Transcription Factors; C493716:Runx2 protein, mouse; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C514061:ihh protein, mouse