Pyruvate dehydrogenase kinase 4 promotes osteoblastic potential of BMP9 by boosting Wnt/beta-catenin signaling in mesenchymal stem cells

作者全名："Yang, Yuan-Yuan; Luo, Hong-Hong; Deng, Yi-Xuan; Yao, Xin-Tong; Zhang, Jie; Su, Yu-Xi; He, Bai-Cheng"

作者地址："[Yang, Yuan-Yuan; Luo, Hong-Hong; Deng, Yi-Xuan; Yao, Xin-Tong; Zhang, Jie; He, Bai-Cheng] Chongqing Med Univ, Sch Pharm, Dept Pharmacol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China; [Yang, Yuan-Yuan; Luo, Hong-Hong; Deng, Yi-Xuan; Yao, Xin-Tong; Zhang, Jie; He, Bai-Cheng] Chongqing Med Univ, Key Lab Biochem & Mol Pharmacol Chongqing, Chongqing 400016, Peoples R China; [Su, Yu-Xi] Chongqing Med Univ, Childrens Hosp, Dept Orthoped, Minist Educ,Key Lab Child Dev & Disorders, Chongqing 400014, Peoples R China"

通信作者："He, BC (通讯作者)，Chongqing Med Univ, Sch Pharm, Dept Pharmacol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China."

来源：INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001031508200001

JCR分区：Q2

影响因子：3.4

年份：2023

卷号：154

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Pyruvate dehydrogenase kinase 4; Bone morphogenetic protein 9; Osteogenic differentiation; Sclerostin; Wnt/beta-catenin

摘要："Bone morphogenetic protein 9 (BMP9) is an effective osteogenic factor and a promising candidate for bone tissue engineering. The osteoblastic potential of BMP9 needs to be further increased to overcome its shortcomings. However, the details of how BMP9 triggers osteogenic differentiation in mesenchymal stem cells (MSCs) are unclear. In this study, we used real-time PCR, western blot, histochemical staining, mouse ectopic bone formation model, immunofluorescence, immunoprecipitation, and chromatin immunoprecipitation to investigate the role of pyruvate dehydrogenase kinase 4 (PDK4) in BMP9-induced osteogenic differentiation of C3H10T1/2 cells, as well as the underlying mechanism. We found that PDK4 was upregulated by BMP9 in C3H10T1/2 cells. BMP9-induced osteogenic markers and bone mass were increased by PDK4 overexpression, but decreased by PDK4 silencing. beta-catenin protein level was increased by BMP9, which was enhanced by PDK overexpression and decreased by PDK4 silencing. BMP9-induced osteogenic markers were reduced by PDK4 silencing, which was almost reversed by beta-catenin overexpression. PDK4 increased the BMP9-induced osteogenic markers, which was almost eliminated by beta-catenin silencing. Sclerostin was mildly decreased by BMP9 or PDK4, and significantly decreased by combined BMP9 and PDK4. In contrast, sclerostin increased significantly when BMP9 was combined with PDK4 silencing. BMP9-induced p-SMAD1/5/9 was increased by PDK4 overexpression, but was reduced by PDK4 silencing. PDK4 interacts with p-SMAD1/5/9 and regulates the sclerostin promoter. These findings suggest that PDK4 can increase the osteogenic potential of BMP9 by enhancing Wnt/beta-catenin signaling via the downregulation of sclerostin. PDK4 may be an effective target to strengthen BMP9-induced osteogenesis."

基金机构：National Natural Science Foundation of China (NSFC) [81572226]; Chongqing Science and Technology Commission Project [cstc2018jcyjAX0143]

基金资助正文："This study was funded by the National Natural Science Foundation of China (NSFC, 81572226) and Chongqing Science and Technology Commission Project (cstc2018jcyjAX0143)."