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      Igf-I extends the chondrogenic potential of human articular chondrocytes in vitro: molecular association between Sox9 and Erk1/2.

      Biochemical Pharmacology

      Cell Differentiation, Biological Markers, metabolism, Cartilage, Articular, drug effects, ultrastructure, physiology, Cells, Cultured, Chondrocytes, Collagen Type II, High Mobility Group Proteins, Humans, Insulin-Like Growth Factor I, pharmacology, Microscopy, Electron, Transmission, Microscopy, Immunoelectron, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, SOX9 Transcription Factor, Transcription Factors

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          Abstract

          Expansion of articular chondrocytes in monolayer culture leads to loss of the unique chondrocyte phenotype and the cells' redifferentiation capacity. Dedifferentiation of chondrocytes in monolayer culture is a challenging problem for autologous chondrocyte transplantation (ACT). It is well established that Igf-I exerts positive anabolic effects on chondrocytes in vivo and in vitro. Accordingly, in this study, we examined whether the anabolic insulin-like growth factor-I (Igf-I) is capable of extending the chondrogenic potential of dedifferentiated chondrocytes in vitro. Chondrocyte monolayers were cultured up to 10 passages. At each passage chondrocytes were stimulated with Igf-I (10ng/ml) and introduced to high-density cultures for up to 7 days. Expression of collagen type II, cartilage-specific proteoglycans, activated caspase-3, integrin beta1, extracellular signal-regulated kinase (Erk) and Sox9 was examined by Western blotting, immunoprecipitation and immunomorphological techniques. Monolayer chondrocytes rapidly lost their differentiated phenotype. When introduced to high-density cultures, only chondrocytes from P1-P4 redifferentiated. In contrast, Igf-I treated cells from P1 up to P7 redifferentiated and formed cartilage-like tissue in high-density culture. P8-P10 cells exhibited apoptotic alterations and produced significantly less matrix. Igf-I markedly increased expression of integrin beta1, Erk and Sox9. Immunoprecipitation revealed that phosphorylated Erk1/2 physically interacts with Sox9 in chondrocyte nuclei, suggesting a previously unreported functional association which was markedly enhanced by Igf-I. Treatment of chondrocyte cultures with Igf-I stabilizes chondrogenic potential, stimulates Sox9 and promotes molecular interactions between Erk and Sox9. These effects appear to be regulated by the integrin/MAPK signaling pathways.

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          Journal
          17010943
          10.1016/j.bcp.2006.08.022

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