Modulation of cartilage differentiation by melanoma inhibiting activity/cartilage-derived retinoic acid-sensitive protein (MIA/CD-RAP)
Modulation of cartilage differentiation by melanoma inhibiting activity/cartilage-derived retinoic acid-sensitive protein (MIA/CD-RAP)
复制标题
DOI：
10.3858/emm.2010.42.3.017
复制
发表时间：
2010-03-31
影响因子：
12.8
通讯作者：
Bosserhoff, Anja-Katrin
中科院分区：
文献类型：
--
作者：
Schubert, Thomas;Schlegel, Jacqueline;Bosserhoff, Anja-Katrin
黑色素瘤抑制活性/软骨衍生的视黄酸敏感蛋白（MIA/CD-RAP）是由恶性黑色素瘤细胞和软骨细胞分泌的小的可溶性蛋白。最近，我们发现MIA/CD-RAP可以调节骨形态发生蛋白（BMP）2诱导的成骨分化成软骨方向。在目前的研究中，我们的目的是找到这种MIA/CD-RAP功能的分子细节。实验排除了MIA通过蛋白质-蛋白质相互作用或调节SMAD信号传导对BMP 2的直接影响。相反，我们发现MIA/CD-RAP抑制ERK信号传导。这种抑制通过MIA/CD-RAP与整联蛋白α 5结合并消除其活性来调节。已知活性ERK信号传导阻断软骨形成分化，并且我们揭示了通过用MIA/CD-RAP或ERK抑制剂PD 098059处理诱导软骨细胞中的聚集蛋白聚糖表达。在体内模型中，我们可以支持MIA/CD-RAP在负面影响成骨分化中的作用。此外，MIA/CD-RAP缺陷型小鼠显示膝关节的关节软骨的钙化软骨层增强和软骨细胞的无序排列。综上所述，我们的数据表明，MIA/CD-RAP稳定软骨分化，并通过调节分化过程中的信号传导过程抑制分化成骨。
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 alpha 5 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.