Regulatory mechanisms of bone metabolism by nervous system

我们建立了新的p38α突变小鼠(sem小鼠)，在编码p38α底物对接位点的区域存在点突变，这是p38α的有限功能丧失模型。在本研究中，我们利用sem小鼠和野生型小鼠(wt小鼠)来研究p38α在骨代谢和神经再生中的生理作用。在骨代谢方面，sem小鼠较wt小鼠表现出更高的骨密度，这可能来自于对破骨细胞分化的抑制。在神经再生方面，我们证实，与wt鼠相比，sem鼠挤压伤后的组织学和功能性神经恢复延迟。为了探讨这些发现的潜在机制，我们检测了坐骨神经挤压伤后的炎症反应，发现肿瘤坏死因子-α、IL-1β、半胱氨酸天冬氨酸蛋白酶-3和Tenascin-C在挤压伤后呈现不同的表达模式。这是第一个在没有使用药物抑制剂的情况下证明p38α在骨代谢和神经再生中的生理作用的研究。

We generated novel p38αmutant mice (sem mice) with a point mutation in the region encoding the p38αsubstrate-docking-site, which serves as a limited loss-of-function model of p38α. In the present study, we utilized sem mice and wild-type littermates (wt mice) to investigate the physiological role of p38αin bone metabolism and in nerve regeneration. In bone metabolism, sem mice showed higher bone density compared with wt mice, which could come from the inhibition of the osteoclast differentiation. In nerve regeneration, we confirmed that histological and functional nerve recovery following crush injury was delayed in sem mice compared with that in wt mice. To investigate the underlying mechanisms of these findings, we examined inflammatory responses of the sciatic nerve, and found that TNF-α, IL-1β, Caspase-3 and Tenascin-C showed different expression patterns following crush injury. This is the first study demonstrating physiological role of p38αin bone metabolism and in nerve regeneration without the use of pharmacological inhibitors.