title: Inhibitor of DNA binding/differentiation helix-loop-helix proteins mediate bone morphogenetic protein-induced osteoblast differentiation of mesenchymal stem cells.
abstract: Bone morphogenetic proteins (BMPs) belong to the TGF-beta superfamily and play an important role in development and in many cellular processes. We have found that BMP-2, BMP-6, and BMP-9 induce the most potent osteogenic differentiation of mesenchymal stem cells. Expression profiling analysis has revealed that the Inhibitors of DNA binding/differentiation (Id)-1, Id-2, and Id-3 are among the most significantly up-regulated genes upon BMP-2, BMP-6, or BMP-9 stimulation. Here, we sought to determine the functional role of these Id proteins in BMP-induced osteoblast differentiation. We demonstrated that the expression of Id-1, Id-2, and Id-3 genes was significantly induced at the early stage of BMP-9 stimulation and returned to basal levels at 3 days after stimulation. RNA interference-mediated knockdown of Id expression significantly diminished the BMP-9-induced osteogenic differentiation of mesenchymal progenitor cells. Surprisingly, a constitutive overexpression of these Id genes also inhibited osteoblast differentiation initiated by BMP-9. Furthermore, we demonstrated that BMP-9-regulated Id expression is Smad4-dependent. Overexpression of the three Id genes was shown to promote cell proliferation that was coupled with an inhibition of osteogenic differentiation. Thus, our findings suggest that the Id helix-loop-helix proteins may play an important role in promoting the proliferation of early osteoblast progenitor cells and that Id expression must be down-regulated during the terminal differentiation of committed osteoblasts, suggesting that a balanced regulation of Id expression may be critical to BMP-induced osteoblast lineage-specific differentiation of mesenchymal stem cells.
authors.affiliation: Molecular Oncology Laboratory, Department of Surgery, and Committe on Genetics, University of Chicago, IL 60637, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.forename: Quan
authors.initials: Q
authors.lastname: Kang
authors.forename: Qing
authors.initials: Q
authors.lastname: Luo
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Weike
authors.initials: W
authors.lastname: Si
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Liu
authors.forename: Hue H
authors.initials: HH
authors.lastname: Luu
authors.forename: Jong Kyung
authors.initials: JK
authors.lastname: Park
authors.forename: Xinmin
authors.initials: X
authors.lastname: Li
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Luo
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Montag
authors.forename: Rex C
authors.initials: RC
authors.lastname: Haydon
authors.forename: Tong-Chuan
authors.initials: TC
authors.lastname: He
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D019070:Cell Lineage; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D020868:Gene Silencing; D055427:Growth Differentiation Factor 2; D051379:Mice; D008809:Mice, Inbred C3H; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000378:metabolism*; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051901:Smad4 Protein; D013234:Stem Cells / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta; D015854:Up-Regulation
chemical_list: C525719:Bmp2 protein, mouse; C525817:Bmp6 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D012313:RNA; D004247:DNA; D000469:Alkaline Phosphatase