Modulation of cartilage differentiation by melanoma inhibiting activity/cartilage-derived retinoic acid-sensitive protein (MIA/CD-RAP).
10.3858/emm.2010.42.3.017
- Author:
Thomas SCHUBERT
1
;
Jacqueline SCHLEGEL
;
Rainer SCHMID
;
Alfred OPOLKA
;
Susanne GRASSEL
;
Martin HUMPHRIES
;
Anja Katrin BOSSERHOFF
Author Information
1. Institute of Pathology, University of Regensburg, Regensburg, Germany. anja.bosserhoff@klinik.uni-regensburg.de
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
bone morphogenetic protein 2;
cartilage;
cell differentiation;
chondrocytes;
MIA protein, human
- MeSH:
Animals;
Bone Morphogenetic Proteins/metabolism;
Cartilage/*cytology/metabolism;
*Cell Differentiation;
Chondrocytes/cytology/enzymology;
Extracellular Matrix Proteins/deficiency/*metabolism;
Extracellular Signal-Regulated MAP Kinases/metabolism;
Humans;
Integrin alpha5/metabolism;
Mesenchymal Stem Cells/cytology/metabolism;
Mice;
Neoplasm Proteins/deficiency/*metabolism;
Osteogenesis;
Protein Binding;
Signal Transduction;
Smad Proteins/metabolism
- From:Experimental & Molecular Medicine
2010;42(3):166-174
- CountryRepublic of Korea
- Language:English
-
Abstract:
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.
