Wu Yougen, Zhou Juan, Li Yinghua, Zhou Yunjiao, Cui Yunqing, Yang Gong, Hong Yang
Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China.
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
PLoS One. 2015 Nov 24;10(11):e0143777. doi: 10.1371/journal.pone.0143777. eCollection 2015.
Rap1A is a member of small G proteins belonging to the Ras family. Recently, an integration of human genome-wide association studies (GWAS) and gene expression profiling study revealed that single-nucleotide polymorphisms (SNPs) within human Rap1A were strongly associated with narrow neck width in women. However, the regulatory role of Rap1A in osteoblasts remains to be elucidated. Here we report that Rap1A is a key regulator in osteoblast differentiation. Rap1A expression and activity were gradually enhanced during the induced differentiation of multipotent mesenchymal progenitor cells (C2C12) and preosteoblastic cells (MC3T3-E1). Knockdown of endogenous Rap1A significantly inhibited the osteogenic marker gene expression and matrix mineralization in cells with osteogenesis. In addition, knockdown of endogenous Rap1A suppressed the activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), while overexpression of Rap1A accelerated osteoblast differentiation and enhanced the phosphorylation of ERK and p38. Taken together, our study suggests that Rap1A regulates osteoblast differentiation through modulating the ERK/p38 signaling.
Rap1A是属于Ras家族的小G蛋白成员。最近，一项整合人类全基因组关联研究（GWAS）和基因表达谱研究表明，人类Rap1A基因内的单核苷酸多态性（SNP）与女性的窄颈宽度密切相关。然而，Rap1A在成骨细胞中的调节作用仍有待阐明。在此，我们报道Rap1A是成骨细胞分化的关键调节因子。在多能间充质祖细胞（C2C12）和前成骨细胞（MC3T3-E1）的诱导分化过程中，Rap1A的表达和活性逐渐增强。敲低内源性Rap1A可显著抑制成骨细胞中骨生成标记基因的表达和基质矿化。此外，敲低内源性Rap1A可抑制细胞外信号调节激酶（ERK）和p38丝裂原活化蛋白激酶（MAPK）的激活，而Rap1A的过表达则加速成骨细胞分化并增强ERK和p38的磷酸化。综上所述，我们的研究表明Rap1A通过调节ERK/p38信号通路来调控成骨细胞分化。
