氨甲环酸与Wnt信号通路中含kringle结构域蛋白的结合对新生小鼠骨密度的影响(英文)

The Effect of AMCA Binding to Kringle Containing Proteins of Wnt Signaling Pathway on Bone Mineral Densities of New Born Mice

最近研究发现Wnt信号通路在骨形成过程中发挥重要作用.Wnt受体如脂蛋白相关蛋白5(lrp5)和孤独受体(Ror2)的缺失或突变导致骨的不正常发育.Dkk是一个分泌型规范Wnt信号系统的抑制剂,通过与脂蛋白相关蛋白5和最近新发现的一种含kringle结构域的蛋白kremen形成三聚体复合物.这种复合物随即被细胞内吞,从而导致细胞表面Wnt受体脂蛋白相关蛋白5水平迅速下降,从而达到抑制Wnt信号通路的目地.通过对kremen和Ror2蛋白序列分析发现kremen和Ror2的胞外部分均含有一个结构上能与赖氨酸结合的kringle结构域.通过给怀孕母鼠注射一种赖氨酸类似物———氨甲环酸来研究kremen和Ror2的kringle结构域上的赖氨酸结合位点被占据对小鼠骨发育的作用.但是,研究结果表明AMCA组和对照组之间的骨密度并没有显著差异,揭示赖氨酸结合位点不参与骨的发育调控.

It is recently found that Wnt signaling pathway plays a crucial role in bone formation. Mutation or deletion of Wnt co-receptor lipoprotein related protein 5 （LRP5） or an orphan receptor tyrosine kinase Ror2 results in abnormal bone development. Dickkopf （Dkk）, a secreted canonical Wnt/catenin signaling inhibitor, is able to form a ternary complex with LRP5/6 and a newly discovered protein, kremen. It mediates endocytosis of LRP5/6, thus inhibits Wnt signaling pathway by removal of cell surface receptors. Based on the structural analysis using protein sequences of kremen and Ror2, we found that each of them has an extracellular kringle domain which is structurally capable for lysine binding. In this study we injected AMCA, a lysine analog, to pregnant mice to see its effect on bone development of new born mice through occupancy of lysine binding sites of kringle domains of Ror2 and kremen. The results showed no significant difference of bone mineral density （BMD） in AMCA treated groups compared with the control group, suggesting that lysine binding sites of kringles are not involved in the process of bone formation.