title: ATF6a, a Runx2-activable transcription factor, is a new regulator of chondrocyte hypertrophy.
abstract: Our previous research has shown that the spliced isoform of XBP1 (XBP1s) is an important downstream mediator of BMP2 and is involved in BMP2-stimulated chondrocyte differentiation. Herein, we report that ATF6 and its cleaved N-terminal cytoplasmic domain (known as ATF6a) are expressed in growth plate chondrocytes. We find that these proteins are differentially induced during BMP2-triggered chondrocyte differentiation. This differential expression probably results from the activation of the ATF6 gene by Runx2 and its repression by the Sox6 transcription factor. Runx2 and Sox6 act through their respective binding elements on the ATF6 gene. When overexpressed, ATF6 and ATF6a intensify chondrogenesis; our studies demonstrate that under the stimulation of ATF6 and ATF6a, chondrocytes tend to be hypertrophied and mineralized, a process leading to bone formation. By contrast, lowering expression of ATF6a by use of its specific siRNA suppresses chondrocyte differentiation. Moreover, ATF6a interacts with Runx2 and augments the Runx2-mediated hypertrophication of chondrocytes. Importantly, overexpression and knockdown of ATF6a during the chondrocyte hypertrophy process also led to altered expressions of IHH and PTHrP (also known as PTHLH). Taken together, these findings indicate that ATF6a favorably controls chondrogenesis and bone formation (1) by acting as a co-factor of Runx2 and enhancing Runx2-incited hypertrophic chondrocyte differentiation, and (2) by affecting IHH and PTHrP signaling.
authors.affiliation: Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China guo.fengjin@gmail.com.
authors.forename: Fengjin
authors.initials: F
authors.lastname: Guo
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: Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Zhimeng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Department of Cell Biology and Genetics, Core Facility of Development Biology, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Orthopaedic Surgery, Qilu Hospital, Shandong University, Jinan 250012, China.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Laboratory of Reproductive Biology, Chongqing Medical University, Chongqing, 400016 China.
authors.forename: Yingxiong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Orthopaedic Surgery and Cell Biology, New York University School of Medicine, New York, 10016 NY, USA.
authors.forename: Chuanju
authors.initials: C
authors.lastname: Liu
mesh_terms: D051702:Activating Transcription Factor 6 / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D049108:Cell Enlargement; D002460:Cell Line; D049109:Cell Proliferation; D019902:Chondrocytes / Q000502:physiology*; D020219:Chondrogenesis; D050659:Core Binding Factor Alpha 1 Subunit / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D010012:Osteogenesis; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D055755:SOXD Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D050659:Core Binding Factor Alpha 1 Subunit; D053823:Hedgehog Proteins; D044162:Parathyroid Hormone-Related Protein; C493716:Runx2 protein, mouse; D055755:SOXD Transcription Factors; C095939:Sox6 protein, mouse; C514061:ihh protein, mouse
keywords: ATF6a; Chondrocyte hypertrophy; Regulation; Transcription factor; UPR