1.Modulation of cartilage differentiation by melanoma inhibiting activity/cartilage-derived retinoic acid-sensitive protein (MIA/CD-RAP).
Thomas SCHUBERT ; Jacqueline SCHLEGEL ; Rainer SCHMID ; Alfred OPOLKA ; Susanne GRASSEL ; Martin HUMPHRIES ; Anja Katrin BOSSERHOFF
Experimental & Molecular Medicine 2010;42(3):166-174
Melanoma inhibiting activity/cartilage-derived retinoic acid-sensitive protein (MIA/CD-RAP) is a small soluble protein secreted from malignant melanoma cells and from chondrocytes. Recently, we revealed that MIA/CD-RAP can modulate bone morphogenetic protein (BMP)2-induced osteogenic differentiation into a chondrogenic direction. In the current study we aimed to find the molecular details of this MIA/CD-RAP function. Direct influence of MIA on BMP2 by protein-protein-interaction or modulating SMAD signaling was ruled out experimentally. Instead, we revealed inhibition of ERK signaling by MIA/CD-RAP. This inhibition is regulated via binding of MIA/CD-RAP to integrin alpha5 and abolishing its activity. Active ERK signaling is known to block chondrogenic differentiation and we revealed induction of aggrecan expression in chondrocytes by treatment with MIA/CD-RAP or PD098059, an ERK inhibitor. In in vivo models we could support the role of MIA/CD-RAP in influencing osteogenic differentiation negatively. Further, MIA/CD-RAP-deficient mice revealed an enhanced calcified cartilage layer of the articular cartilage of the knee joint and disordered arrangement of chondrocytes. Taken together, our data indicate that MIA/CD-RAP stabilizes cartilage differentiation and inhibits differentiation into bone potentially by regulating signaling processes during differentiation.
Animals
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Bone Morphogenetic Proteins/metabolism
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Cartilage/*cytology/metabolism
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*Cell Differentiation
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Chondrocytes/cytology/enzymology
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Extracellular Matrix Proteins/deficiency/*metabolism
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Extracellular Signal-Regulated MAP Kinases/metabolism
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Humans
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Integrin alpha5/metabolism
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Mesenchymal Stem Cells/cytology/metabolism
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Mice
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Neoplasm Proteins/deficiency/*metabolism
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Osteogenesis
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Protein Binding
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Signal Transduction
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Smad Proteins/metabolism