The CREB-Smad6-Runx2 axis contributes to the impaired osteogenesis potential of bone marrow stromal cells in fibrous dysplasia of bone
The CREB-Smad6-Runx2 axis contributes to the impaired osteogenesis potential of bone marrow stromal cells in fibrous dysplasia of bone
复制标题
CREB-Smad6-Runx2轴导致骨纤维发育不良中骨髓基质细胞的成骨潜力受损
DOI：
10.1002/path.4033
复制
发表时间：
2012-09-01
影响因子：
7.3
通讯作者：
Tang, Ting-Ting
中科院分区：
文献类型：
--
作者：
Fan, Qi-Ming;Yue, Bing;Tang, Ting-Ting
纤维性发育不良（FD）的特征是正常骨被异常的纤维骨组织替代。这种疾病是由于激活GNAS基因中的错义突变和由此产生的cAMP过量产生。然而，导致FD发病机制的信号通路仍然未知。本研究从FD患者的病变部位分离携带GNAS R201 H突变的骨髓基质细胞（BMSCs）。观察到cAMP积累、增殖增强和成骨潜能受损。建立了外源性cAMP处理和慢病毒GNAS R201 H感染两种细胞模型，模拟FD的病理状态，探讨FD的发病机制。结果提示CREB-Smad 6-Runx 2轴参与了FD表型BMSCs成骨功能障碍。我们证实了FD病变来源的BMSC的结果，并观察到慢病毒GNAS（R201 H）感染的BMSC的受损的成骨潜能通过CREB-Smad 6-Runx 2轴的调节在体外恢复。这项研究提供了有用的洞察信号通路参与FD表型，有利于解剖FD的分子发病机制和测试的新疗法。版权所有（C）2012大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Fibrous dysplasia (FD) is characterized by the replacement of normal bone with abnormal fibro-osseous tissue. This disorder is due to activating missense mutations in the GNAS gene and resultant over-production of cAMP. However, the signalling pathways that contribute to FD pathogenesis remain unknown. In the current study, bone marrow stromal cells (BMSCs) carrying GNAS R201H mutation were isolated from lesion site of FD patients. cAMP accumulation, enhanced proliferation and impaired osteogenesis potential were observed. Two cell models, BMSCs treated with excess exogenous cAMP and BMSCs infected with lentivirus GNAS R201H, were established to model the pathological conditions of FD and used to investigate its pathogenesis. The results suggest that the CREB-Smad6-Runx2 axis is involved in osteogenesis dysfunction of BMSCs with the FD phenotype. We confirmed the results in FD lesion-derived BMSCs and observed that the impaired osteogenesis potential of BMSCs infected with lentivirus GNAS (R201H) was recovered in vitro through modulation of the CREB-Smad6-Runx2 axis. This study provides useful insight into the signalling pathways involved in the FD phenotype and facilitates dissection of the molecular pathogenesis of FD and testing of novel therapies. Copyright (C) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.