Institute of Pathology, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
Exp Mol Med. 2010 Mar 31;42(3):166-74. doi: 10.3858/emm.2010.42.3.017.
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.
黑色素抑制活性/软骨衍生的维甲酸敏感蛋白（MIA/CD-RAP）是一种从小鼠黑色素瘤细胞和软骨细胞分泌的小可溶性蛋白。最近，我们发现 MIA/CD-RAP 可以调节骨形态发生蛋白（BMP）2 诱导的成骨向软骨方向分化。在本研究中，我们旨在寻找 MIA/CD-RAP 功能的分子细节。实验排除了 MIA 通过蛋白-蛋白相互作用直接影响 BMP2 或调节 SMAD 信号的可能性。相反，我们发现 MIA/CD-RAP 抑制 ERK 信号。这种抑制是通过 MIA/CD-RAP 与整合素 α5 结合并使其失活来调节的。已知活性 ERK 信号会阻止软骨分化，我们通过用 MIA/CD-RAP 或 PD098059（一种 ERK 抑制剂）处理软骨细胞，发现 aggrecan 表达的诱导。在体内模型中，我们可以支持 MIA/CD-RAP 在负向影响成骨分化中的作用。此外，MIA/CD-RAP 缺陷型小鼠的膝关节关节软骨的钙化软骨层增强，软骨细胞排列紊乱。总之，我们的数据表明 MIA/CD-RAP 通过调节分化过程中的信号转导过程来稳定软骨分化并抑制向骨的分化。
