Hey1 basic helix-loop-helix protein plays an important role in mediating BMP9-induced osteogenic differentiation of mesenchymal progenitor cells.
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.
Sharff
Katie A
KA
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.
Song
Wen-Xin
WX
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.
Luo
Xiaoji
X
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.
Tang
Ni
N
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.
Luo
Jinyong
J
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.
Chen
Jin
J
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.
Bi
Yang
Y
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.
He
Bai-Cheng
BC
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.
Huang
Jiayi
J
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.
Li
Xinmin
X
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.
Jiang
Wei
W
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.
Zhu
Gao-Hui
GH
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.
Su
Yuxi
Y
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.
He
Yun
Y
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.
Shen
Jikun
J
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.
Wang
Yi
Y
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.
Chen
Liang
L
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.
Zuo
Guo-Wei
GW
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.
Liu
Bo
B
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.
Pan
Xiaochuan
X
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.
Reid
Russell R
RR
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.
Luu
Hue H
HH
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.
Haydon
Rex C
RC
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.
He
Tong-Chuan
TC
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.
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
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