Transcriptional Upregulation of DDR2 by ATF4 Facilitates Osteoblastic Differentiation Through p38 MAPK-Mediated Runx2 Activation
Transcriptional Upregulation of DDR2 by ATF4 Facilitates Osteoblastic Differentiation Through p38 MAPK-Mediated Runx2 Activation
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DOI：
10.1002/jbmr.159
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发表时间：
2010-11-01
影响因子：
6.2
通讯作者：
Wang, Fung-Fang
中科院分区：
文献类型：
--
作者：
Lin, Kuan-Liang;Chou, Ching-Heng;Wang, Fung-Fang
胶原蛋白受体盘状结构域受体酪氨酸激酶（DDR2）缺陷在小鼠和人类中导致侏儒症和短肢，其机制尚不清楚。在此，我们报告了DDR2是成骨细胞分化的关键调节因子，在诱导成骨细胞分化的早期阶段，DDR2 mRNA表达增加。在人类骨关节炎膝关节的软骨下骨中，在小鼠胚胎的成骨细胞中检测到DDR2。在成骨细胞分化过程中，从E11到E15发现DDR2表达先于骨钙素（OCN），并且与Runx 2表达一致。激活转录因子4（ATF 4）增强DDR2 mRNA表达，并且ATF 4表达的敲低延迟DDR2诱导。EBP β与ATF 4结合并协同刺激DDR2转录，因此，缺乏C/EBP β结合的ATF 4突变体不能反式激活DDR2。DDR2的过表达增加成骨细胞特异性基因表达。相反，DDR2的敲低抑制成骨标记基因表达和诱导成骨过程中的基质矿化。Runx 2和OCN启动子的诱导激活我们的研究结果共同揭示了ATF 4通过与C/EBP β结合转录上调DDR2表达和DDR2的途径，进而通过p38 MAPK激活Runx 2以促进成骨细胞分化（C）2010年美国骨与矿物研究学会
Deficiency of the collagen receptor discoidin domain receptor tyrosine kinase (DDR2) in mice and humans results in dwarfism and short limbs of which the mechanism remains unknown Here we report that DDR2 is a key regulator of osteoblast differentiation DDR2 mRNA expression was increased at an early stage of induced osteoblast differentiation In the subchondral bone of human osteoarthritic knee DDR2 was detected in osteoblastic cells In mouse embryos DDR2 expression was found from El 1 to El 5 preceding osteocalcin (OCN) and coinciding with Runx2 expression Activating transcription factor 4 (ATF4) enhanced DDR2 mRNA expression and knockdown of ATF4 expression delayed DDR2 induction during osteoblast differentiation A CCAAT/enhancer binding protein (C/EBP) binding site at 1150 bp in the DDR2 promoter was required for ATF4 mediated DDR2 activation C/EBP beta bound to and cooperated with ATF4 in stimulating DDR2 transcription, accordingly the ATF4 mutants deficient of C/EBP beta binding were incapable of transactivating DDR2 Overexpression of DDR2 increased osteoblast specific gene expression Conversely knockdown of DDR2 suppressed osteogenic marker gene expression and matrix mineralization during the induced osteogenesis The stimulation of p38 MAPK by DDR2 was required for DDR2-induced activation of Runx2 and OCN promoters Together our findings uncover a pathway in which ATF4 by binding to C/EBP beta transcriptionally upregulates DDR2 expression and DDR2, in turn activates Runx2 through p38 MAPK to promote osteoblast differentiation (C) 2010 American Society for Bone and Mineral Research