title: Hey1 basic helix-loop-helix protein plays an important role in mediating BMP9-induced osteogenic differentiation of mesenchymal progenitor cells.
abstract: Pluripotent mesenchymal stem cells (MSCs) are bone marrow stromal progenitor cells that can differentiate into osteogenic, chondrogenic, adipogenic, and myogenic lineages. We previously demonstrated that bone morphogenetic protein (BMP) 9 is one of the most potent and yet least characterized BMPs that are able to induce osteogenic differentiation of MSCs both in vitro and in vivo. Here, we conducted gene expression-profiling analysis and identified that Hey1 of the hairy/Enhancer of split-related repressor protein basic helix-loop-helix family was among the most significantly up-regulated early targets in BMP9-stimulated MSCs. We demonstrated that Hey1 expression was up-regulated at the immediate early stage of BMP9-induced osteogenic differentiation. Chromatin immunoprecipitation analysis indicated that Hey1 may be a direct target of the BMP9-induced Smad signaling pathway. Silencing Hey1 expression diminished BMP9-induced osteogenic differentiation both in vitro and in vivo and led to chondrogenic differentiation. Likewise, constitutive Hey1 expression augmented BMP9-mediated bone matrix mineralization. Hey1 and Runx2 were shown to act synergistically in BMP9-induced osteogenic differentiation, and Runx2 expression significantly decreased in the absence of Hey1, suggesting that Runx2 may function downstream of Hey1. Accordingly, the defective osteogenic differentiation caused by Hey1 knockdown was rescued by exogenous Runx2 expression. Thus, our findings suggest that Hey1, through its interplay with Runx2, may play an important role in regulating BMP9-induced osteoblast lineage differentiation of MSCs.
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Katie A
authors.initials: KA
authors.lastname: Sharff
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637; Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Wen-Xin
authors.initials: WX
authors.lastname: Song
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637; Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Xiaoji
authors.initials: X
authors.lastname: Luo
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637; Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Ni
authors.initials: N
authors.lastname: Tang
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637; Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Jinyong
authors.initials: J
authors.lastname: Luo
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637; Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637; Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Yang
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637; Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Bai-Cheng
authors.initials: BC
authors.lastname: He
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637; Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Huang
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Li
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637; Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Gao-Hui
authors.initials: GH
authors.lastname: Zhu
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637; Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Su
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637; Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Yun
authors.initials: Y
authors.lastname: He
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Jikun
authors.initials: J
authors.lastname: Shen
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637; Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637; Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637; Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Guo-Wei
authors.initials: GW
authors.lastname: Zuo
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637; Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Pan
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Reid
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637.
authors.forename: Hue H
authors.initials: HH
authors.lastname: Luu
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637. Electronic address: rhaydon@surgery.bsd.uchicago.edu.
authors.forename: Rex C
authors.initials: RC
authors.lastname: Haydon
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637; Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637, the Key Laboratory of Diagnostic Medicine designated by Chinese Ministry of Education and The Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China, the Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, and the Department of Radiology, The University of Chicago Medical Center, Chicago, Illinois 60637. Electronic address: tche@surgery.bsd.uchicago.edu.
authors.forename: Tong-Chuan
authors.initials: TC
authors.lastname: He
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D055427:Growth Differentiation Factor 2 / Q000235:genetics / Q000378:metabolism*; D055412:Growth Differentiation Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D051785:Smad Proteins; C525887:GDF2 protein, human; C526108:Gdf2 protein, mouse; C485631:HEY1 protein, human; C120420:Hey1 protein, mouse; C493709:RUNX2 protein, human; C493716:Runx2 protein, mouse