Abstract
The role of the bone morphogenetic protein (BMP)-signaling mediator Smad1 in osteogenic or chondrogenic differentiation was investigated in murine parental mesenchymal progenitors C3H10T1/2 and its derivatives constitutively expressing BMP-2 (C3H10T1/2-BMP-2) and, therefore, undergo BMP-mediated osteogenic/ chondrogenic development. The functions of the three Smad1 domains, that is, the N-terminal (MH1) domain, the C-terminal (MH2) domain, and the midregional proline-rich linker domain, were documented and compared with full-length Smadl. We showed that expression of the MH2 domain in parental C3H10T1/2 cells was sufficient to initiate osteogenic differentiation. Interestingly, MH1 was sufficient to initiate transcription of osteogenic marker genes like the osteocalcin or parathyroid hormone/parathyroid hormone-related protein (PTH/PTHrP) receptor. However, MH1 interfered with the histologically distinct formation of osteoblast-like cells. A dominant-negative effect on MH2-mediated osteogenic development in C3H10T1/2 cells was observed by the dose-dependent trans-expression of the midregional linker domain. Importantly, in contrast to osteogenic differentiation, Smad1 and its domains do not mimic or interfere with BMP-2-dependent chondrogenic development as monitored by the inability of MH2 to give rise to histologically distinct chondrocytes in parental C3H10T1/2 cells and by the inefficiency of the MH1 or linker domain to interfere with BMP-2-mediated chondrogenic differentiation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkaline Phosphatase / metabolism
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Animals
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Biomarkers
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Bone Morphogenetic Protein 2
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Bone Morphogenetic Proteins / genetics
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Bone Morphogenetic Proteins / pharmacology*
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Cell Differentiation / drug effects*
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Cell Line
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Cell Lineage / drug effects
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Chondrocytes / cytology
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Chondrocytes / drug effects
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Chondrocytes / metabolism
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Chondrogenesis / drug effects*
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Gene Expression Regulation
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Genes, Reporter
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Mesoderm / cytology
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Mesoderm / drug effects*
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Mesoderm / metabolism
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Mice
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Osteoblasts / cytology
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Osteoblasts / drug effects
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Osteoblasts / metabolism
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Osteogenesis / drug effects*
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Peptide Fragments / chemistry
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Protein Structure, Tertiary
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RNA, Messenger / analysis
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RNA, Messenger / genetics
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Recombinant Proteins / metabolism
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Signal Transduction / drug effects
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Smad Proteins
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Smad1 Protein
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Stem Cells / cytology
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Stem Cells / drug effects
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Stem Cells / metabolism
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Trans-Activators / chemistry
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transforming Growth Factor beta*
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Xenopus
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Xenopus Proteins
Substances
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Biomarkers
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Bmp2 protein, mouse
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Bone Morphogenetic Protein 2
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Bone Morphogenetic Proteins
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DNA-Binding Proteins
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MXD1 protein, Xenopus
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Peptide Fragments
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RNA, Messenger
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Recombinant Proteins
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Smad Proteins
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Smad1 Protein
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Smad1 protein, mouse
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Trans-Activators
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Transforming Growth Factor beta
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Xenopus Proteins
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Alkaline Phosphatase