Mechanism of regulation of bone metabolism by insulin receptor substrates (IRS-1 and IRS-2)

胰岛素受体底物（IRS-1和IRS-2）是胰岛素和类胰岛素生长因子I（IGF-I）的体内信号的必要条件，是骨骼代谢的代谢调节器。对IRS-1和IRS-2的生理作用进行调查，对小鼠缺失的IRS-1或IRS-2在体内和体外的骨骼组织进行调查。老鼠失去了IRS-1基因（IRS-1 ^<-->老鼠）显示了低弯曲的骨质疏松症在两个骨骼形成和还原中的退化。这是对骨骼发育中无自然功能和RANKL诱导的影响。IRS-1 ^<-->老鼠还展示了对碎片愈合能力的影响，以抑制中间细胞和细胞的增加，建议IRS-1是修复骨骼的必要条件。在另一边，IRS-2 ^<-->老鼠表现出骨质疏松症，退化的骨骼形成和退化的骨骼复原。这是对骨质中受影响的无代谢功能和增强的RANKL表达的结论。我们认为，这些无生物行为是由两种蛋白质结合起来的，这些蛋白质具有不同的生物作用：IRS-1和IRS-2。前体是必需的，以维持骨骼通过向上调节anabolic功能和RANKL表达式来扭转，而更晚的是需要保持anabolic功能对catabolic功能的预测。

Insulin receptor substrates (IRS-1 and IRS-2) are essential for intracellular signaling by insulin and insulin-like growth factor-I (IGF-I) , anabolic regulators of bone metabolism. To investigate the physiological roles of IRS-1 and IRS-2, weinvestigated the bone tissue of mice lacking IRS-1 or IRS-2 in vivo and in vitro. Mice lacking the IRS-1 gene (IRS-1^<-・-> mice) showed low-turnover osteopenia with the decrease in both bone formation and resorption. This was due to the impairment of the anabolic function and RANKL induction in osteoblasts. IRS-1^<-・-> mice also showed the impairment of the fracture healing ability by inhibiting the proliferation of mesenchymal cells and chondrocytes, suggesting that IRS-1 is essential for bone repair. On the other hand, IRS-2^<-・-> mice showed osteopenia with decreased bone formation and increased bone resorption. This was due to the impaired anabolic function and enhanced RANKL expression in osteoblasts. We propose that these anabolic actions are maintained as an integration of two proteins that have distinct biological roles in osteoblasts: IRS-1 and IRS-2. The former is essential to maintain bone turnover by up-regulating anabolic function and RANKL expression, while the latter is needed to keep the predominance of the anabolic function over the catabolic function.