The role of COX-2 in mediating the effect of PTEN on BMP9 induced osteogenic differentiation in mouse embryonic fibroblasts
The role of COX-2 in mediating the effect of PTEN on BMP9 induced osteogenic differentiation in mouse embryonic fibroblasts
复制标题
COX-2在PTEN对BMP9诱导小鼠胚胎成纤维细胞成骨分化的影响中的作用
DOI：
10.1016/j.biomaterials.2014.08.016
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发表时间：
2014-12-01
期刊：
影响因子：
14
通讯作者：
He, Bai-Cheng
中科院分区：
文献类型：
--
作者：
Huang, Jun;Yuan, Shuang-Xue;He, Bai-Cheng
小鼠胚胎成纤维细胞（MEFs）是一种多能祖细胞（MPC），可分化为成骨细胞和成脂细胞。抑癌基因PTEN可能通过与考克斯-2相互作用参与骨发育的调控。BMP 9是最强的成骨BMP，可上调MPC中的考克斯-2。PTEN是否参与BMP 9诱导的MPC成骨分化仍不清楚。本研究旨在探讨PTEN对BMP 9诱导的MPC成骨分化的影响及其可能的机制。我们发现，BMP 9下调PTEN，和PTEN抑制剂（VO）有效地增加不同的成骨标志物诱导的BMP 9在MEFs中。外源性PTEN表达明显抑制BMP 9诱导的异位成骨。在机制上，我们发现VO可以显著增强BMP 9诱导的BMPs/Smads信号转导，而对细胞周期没有实质性影响。进一步分析表明，VO可促进BMP 9诱导的MEFs中考克斯-2的表达，这种作用可被PI 3 K抑制剂所消除。此外，考克斯-2敲低取消了VO对MMP 9诱导的MEFs中ALP活性的影响。我们的研究结果表明，PTEN在BMP 9诱导的MPC成骨分化中起重要作用，这可能是通过PTEN/PI 3 K/Akt信号转导调节考克斯-2的表达。(C)2014爱思唯尔有限公司版权所有。
Mouse embryonic fibroblasts (MEFs) are multi-potent progenitor cells (MPCs), can differentiate into different lineages, such as osteogenic, and adipogenic. PTEN, a tumor suppressor, may be involved in regulating bone development through interacting with COX-2. BMP9, the most potent osteogenic BMPs, can up-regulate COX-2 in MPCs. Whether PTEN is involved in BMP9 induced osteogenic differentiation in MPCs remains unknown. The goal of this investigation is to identify the effect of PTEN on BMP9-induced osteogenic differentiation in MPCs and dissect the possible mechanism underlay this. We found that BMP9 down-regulates PTEN, and PTEN inhibitor (VO) effectively increases different osteogenic markers induced by BMP9 in MEFs. Exogenous expression of PTEN inhibits BMP9 induced ectopic bone formation apparently. Mechanistically, we found that VO can enhance BMP9 induced BMPs/Smads signaling prominently without no substantial effects on cell cycle. Further analysis indicates that VO can promote BMP9-induced expression of COX-2 in MEFs, which can be eliminated by PI3K inhibitor. Additionally, COX-2 knockdown abolishes the effect of VO on BMP9-induced ALP activities in MEFs. Our findings suggest that PTEN plays an important role in regulating BMP9 induced osteogenic differentiation in MPCs, which may be mediated by PTEN/PI3K/Akt signaling to modulate the expression of COX-2. (C) 2014 Elsevier Ltd. All rights reserved.