Modulation of cartilage differentiation by melanoma inhibiting activity/cartilage-derived retinoic acid-sensitive protein (MIA/CD-RAP).
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.
Schubert
Thomas
T
Institute of Pathology, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
Schlegel
Jacqueline
J
Schmid
Rainer
R
Opolka
Alfred
A
Grassel
Susanne
S
Humphries
Martin
M
Bosserhoff
Anja-Katrin
AK
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002356:Cartilage / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation; D019902:Chondrocytes / Q000166:cytology / Q000201:enzymology; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D039482:Integrin alpha5 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000172:deficiency / Q000378:metabolism*; D010012:Osteogenesis; D011485:Protein Binding; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D016326:Extracellular Matrix Proteins; D039482:Integrin alpha5; C090059:MIA protein, human; C513263:Mia protein, mouse; D009363:Neoplasm Proteins; D051785:Smad Proteins; D048049:Extracellular Signal-Regulated MAP Kinases