Exp Mol Med.  2010 Mar;42(3):166-174. 10.3858/emm.2010.42.3.017.

Modulation of cartilage differentiation by melanoma inhibiting activity/cartilage-derived retinoic acid-sensitive protein (MIA/CD-RAP)

• Schubert T
• Schlegel J
• Schmid R
• Opolka A
• Grassel S
• Humphries
• Bosserhoff AK

• KMID: 946649
• DOI: http://doi.org/10.3858/emm.2010.42.3.017

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.

Keyword

bone morphogenetic protein 2; cartilage; cell differentiation; chondrocytes; MIA protein, human

MeSH Terms

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