Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, People's Republic of China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, People's Republic of China.
Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, People's Republic of China; Department of Orthopedic Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China.
Biomaterials. 2014 Dec;35(36):9649-59. doi: 10.1016/j.biomaterials.2014.08.016. Epub 2014 Aug 29.
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.
小鼠胚胎成纤维细胞（MEFs）是多能祖细胞（MPCs），可以分化为不同的谱系，如成骨细胞和脂肪细胞。肿瘤抑制因子 PTEN 可能通过与 COX-2 相互作用参与调节骨骼发育。BMP9 是最有效的成骨 BMPs，可以上调 MPCs 中的 COX-2。PTEN 是否参与 BMP9 诱导的 MPC 成骨分化尚不清楚。本研究的目的是确定 PTEN 对 BMP9 诱导的 MPC 成骨分化的影响，并探讨其潜在机制。我们发现 BMP9 下调 PTEN，PTEN 抑制剂（VO）可有效增加 BMP9 在 MEFs 中诱导的不同成骨标志物。外源性表达 PTEN 可明显抑制 BMP9 诱导的异位骨形成。机制上，我们发现 VO 可以显著增强 BMP9 诱导的 BMPs/Smads 信号，而对细胞周期没有实质性影响。进一步分析表明，VO 可以促进 BMP9 在 MEFs 中诱导 COX-2 的表达，而 PI3K 抑制剂可以消除这种作用。此外，COX-2 敲低可消除 VO 对 MEFs 中 BMP9 诱导的 ALP 活性的影响。我们的研究结果表明，PTEN 在调节 MPC 中 BMP9 诱导的成骨分化中起重要作用，这可能是通过 PTEN/PI3K/Akt 信号通路来调节 COX-2 的表达。
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