The bone morphogenetic protein 2 signaling mediator Smad1 participates predominantly in osteogenic and not in chondrogenic differentiation in mesenchymal progenitors C3H10T1/2

• Published in: Journal of bone and mineral research 2000-10, Vol.15 (10), p.1889-1899
• Main Authors: Ju, W, Hoffmann, A, Verschueren, K, Tylzanowski, P, Kaps, C, Gross, G, Huylebroeck, D
• Format: Article
• Language: English
• Subjects: Alkaline Phosphatase - metabolism; Animals; Biomarkers; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins - genetics; Bone Morphogenetic Proteins - pharmacology; Cell Differentiation - drug effects; Cell Line; Cell Lineage - drug effects; Chondrocytes - cytology; Chondrocytes - drug effects; Chondrocytes - metabolism; Chondrogenesis - drug effects; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression Regulation; Genes, Reporter; Mesoderm - cytology; Mesoderm - drug effects; Mesoderm - metabolism; Mice; Osteoblasts - cytology; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteogenesis - drug effects; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - metabolism; Protein Structure, Tertiary; Recombinant Proteins - metabolism; RNA, Messenger - analysis; RNA, Messenger - genetics; Signal Transduction - drug effects; Smad Proteins; Smad1 Protein; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - metabolism; Trans-Activators - chemistry; Trans-Activators - genetics; Trans-Activators - metabolism; Transforming Growth Factor beta; Xenopus; Xenopus Proteins
• ISSN: 0884-0431
• DOI: 10.1359/jbmr.2000.15.10.1889

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.