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Tuli, R, Tuli, S, Nandi, S, Huang, X, Manner, PA, Hozack, WJ, Danielson, KG, Hall, DJ and Tuan, RS (2003) Transforming growth factor-beta-mediated chondrogenesis of human mesenchymal progenitor cells involves N-cadherin and mitogen-activated protein kinase and Wnt signaling cross-talk. J. Biol. Chem. 278:41227-36


The multilineage differentiation potential of adult tissue-derived mesenchymal progenitor cells (MPCs), such as those from bone marrow and trabecular bone, makes them a useful model to investigate mechanisms regulating tissue development and regeneration, such as cartilage. Treatment with transforming growth factor-beta (TGF-beta) superfamily members is a key requirement for the in vitro chondrogenic differentiation of MPCs. Intracellular signaling cascades, particularly those involving the mitogen-activated protein (MAP) kinases, p38, ERK-1, and JNK, have been shown to be activated by TGF-betas in promoting cartilage-specific gene expression. MPC chondrogenesis in vitro also requires high cell seeding density, reminiscent of the cellular condensation requirements for embryonic mesenchymal chondrogenesis, suggesting common chondro-regulatory mechanisms. Prompted by recent findings of the crucial role of the cell adhesion protein, N-cadherin, and Wnt signaling in condensation and chondrogenesis, we have examined here their involvement, as well as MAP kinase signaling, in TGF-beta1-induced chondrogenesis of trabecular bone-derived MPCs. Our results showed that TGF-beta1 treatment initiates and maintains chondrogenesis of MPCs through the differential chondro-stimulatory activities of p38, ERK-1, and to a lesser extent, JNK. This regulation of MPC chondrogenic differentiation by the MAP kinases involves the modulation of N-cadherin expression levels, thereby likely controlling condensation-like cell-cell interaction and progression to chondrogenic differentiation, by the sequential up-regulation and progressive down-regulation of N-cadherin. TGF-beta1-mediated MAP kinase activation also controls WNT-7A gene expression and Wnt-mediated signaling through the intracellular beta-catenin-TCF pathway, which likely regulates N-cadherin expression and subsequent N-cadherin-mediated cell-adhesion complexes during the early steps of MPC chondrogenesis.


PubMed Online version:10.1074/jbc.M305312200


Animals; Blotting, Western; Bone and Bones/cytology; Cadherins/metabolism; Cell Adhesion; Cell Differentiation; Cell Lineage; Cells, Cultured; Chondrocytes/cytology; Chondrocytes/metabolism; Cytoskeletal Proteins/metabolism; Enzyme Activation; Enzyme Inhibitors/pharmacology; Gene Expression Regulation; Genes, Reporter; Humans; Immunohistochemistry; MAP Kinase Signaling System; Mice; Mice, Inbred C3H; Mitogen-Activated Protein Kinases/metabolism; Protein Biosynthesis; Proteins/genetics; Proto-Oncogene Proteins/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Stem Cells/metabolism; Sulfates/metabolism; Time Factors; Trans-Activators/metabolism; Transforming Growth Factor beta/metabolism; Up-Regulation; Wnt Proteins; Zebrafish Proteins; beta Catenin; p38 Mitogen-Activated Protein Kinases



Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status


GO:0005634: nucleus



Figure 7B

CACAO 11844


GO:0005737: cytoplasm



Figure 7B

CACAO 11845


GO:0090263: positive regulation of canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion


Figure 7B

CACAO 11860


See also


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