National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, China.
Orthopedic Research Institution, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, China.
J Mater Chem B. 2024 Aug 7;12(31):7591-7603. doi: 10.1039/d4tb01335b.
An increasing number of studies demonstrate that biphasic calcium phosphate (BCP) ceramics can induce bone regeneration. However, the underlying molecular mechanisms involved are still poorly understood. This work was proposed to investigate how PI3K/AKT/mTOR signaling influenced the osteogenesis mediated by BCP ceramics. The results showed that incubation with BCP ceramics promoted the proliferation of murine bone marrow-derived mesenchymal stem cells (BMSCs) in a time-dependent manner. The resulting cell proliferation was then suppressed by the selective inhibition of either PI3K, AKT, or mTOR signaling activation. Next, we confirmed that BCP ceramics up-regulated the phosphorylation levels of AKT and mTOR in BMSCs, suggesting the ability of BCP ceramics to drive the activation of PI3K/AKT/mTOR signaling in BMSCs. Furthermore, the blockade of PI3K/AKT/mTOR signaling prevented BCP ceramics-induced osteogenic differentiation and pro-angiogenesis of BMSCs by down-regulating the expression of genes encoding OPN, RUNX2 or VEGF. Moreover, the PI3K/AKT/mTOR signaling blockade suppressed stem cell infiltration and new bone formation in the implants following intra-muscular implantation of BCP ceramics in mice. Therefore, our results suggested that PI3K/AKT/mTOR signaling played a critical regulatory role in BCP ceramic-induced osteogenesis.
越来越多的研究表明双相磷酸钙（BCP）陶瓷能诱导骨再生。然而，其中涉及的潜在分子机制仍知之甚少。本研究旨在探讨 PI3K/AKT/mTOR 信号通路如何影响 BCP 陶瓷介导的成骨作用。结果表明，BCP 陶瓷孵育能时间依赖性促进小鼠骨髓间充质干细胞（BMSCs）的增殖。随后，PI3K、AKT 或 mTOR 信号通路的选择性抑制能抑制细胞增殖。接下来，我们证实 BCP 陶瓷能上调 BMSCs 中 AKT 和 mTOR 的磷酸化水平，提示 BCP 陶瓷能驱动 BMSCs 中 PI3K/AKT/mTOR 信号通路的激活。此外，PI3K/AKT/mTOR 信号通路的阻断通过下调 OPN、RUNX2 或 VEGF 编码基因的表达，阻止了 BCP 陶瓷诱导的 BMSCs 成骨分化和促血管生成。此外，PI3K/AKT/mTOR 信号通路的阻断抑制了 BCP 陶瓷在小鼠肌肉内植入后植入物中干细胞的浸润和新骨形成。因此，我们的研究结果表明，PI3K/AKT/mTOR 信号通路在 BCP 陶瓷诱导的成骨作用中起着关键的调节作用。
