Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115; email:
Annu Rev Cell Dev Biol. 2013;29:63-79. doi: 10.1146/annurev-cellbio-101512-122347. Epub 2013 May 31.
Mitogen-activated protein kinases (MAPKs) are ancient signal transducers well characterized as mediators of inflammation and neoplastic transformation. Recent work has expanded our understanding of their developmental functions, particularly in the regulation of bone mass via control of osteoblast differentiation. Here, we review the functions of MAPK pathways in osteoblasts, including a consideration of MAPK substrates. In particular, MAPKs function to regulate the key transcriptional mediators of osteoblast differentiation, with ERK and p38 MAPKs phosphorylating RUNX2, the master regulator of osteoblast differentiation. ERK also activates RSK2, which in turn phosphorylates ATF4, a transcriptional regulator of late-stage osteoblast synthetic functions. The MAP3Ks and MAP2Ks upstream of MAPKs have also been investigated, and significant differences have been found in the wiring of MAPK pathways in osteoblasts relative to other tissues. Thus, the investigation of MAPKs in osteoblasts has both revealed critical mechanisms for the maintenance of bone mass and added to our understanding of how the individual components of MAPK pathways function in concert in a complex in vivo system.
丝裂原活化蛋白激酶（MAPK）是一种古老的信号转导蛋白，作为炎症和肿瘤转化的介质而被广泛研究。最近的研究工作扩展了我们对其发育功能的理解，特别是在通过控制成骨细胞分化来调节骨量方面。在这里，我们综述了 MAPK 通路在成骨细胞中的功能，包括对 MAPK 底物的考虑。特别是，MAPK 调节成骨细胞分化的关键转录调节因子，ERK 和 p38 MAPK 磷酸化 RUNX2，这是成骨细胞分化的主要调节因子。ERK 还激活 RSK2，RSK2 又磷酸化 ATF4，ATF4 是成骨细胞合成功能晚期的转录调节因子。MAPK 的上游 MAP3Ks 和 MAP2Ks 也已被研究，与其他组织相比，在成骨细胞中 MAPK 通路的布线存在显著差异。因此，对成骨细胞中 MAPK 的研究不仅揭示了维持骨量的关键机制，而且加深了我们对 MAPK 通路中各个成分如何在复杂的体内系统中协同发挥作用的理解。
