Department of Cell Biology and Genetics, Xi'an Jiaotong University Health Science Center, Xi'an, China.
Department of Clinical Hematology, Second Affiliated Hospital, Xi'an Jiaotong University Health Science Center, Xi'an, China.
J Cell Mol Med. 2020 Aug;24(16):9428-9438. doi: 10.1111/jcmm.15605. Epub 2020 Jul 6.
Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into a variety of cell types. Bortezomib, the first approved proteasome inhibitor used for the treatment of multiple myeloma (MM), has been shown to induce osteoblast differentiation, making it beneficial for myeloma bone disease. In the present study, we aimed to investigate the effects and underlying mechanisms of bortezomib on the cell cycle during osteogenic differentiation. We confirmed that low doses of bortezomib can induce MSCs towards osteogenic differentiation, but high doses are toxic. In the course of bortezomib-induced osteogenic differentiation, we observed cell cycle exit characterized by G /G phase cell cycle arrest with a significant reduction in cell proliferation. Additionally, we found that the cell cycle exit was tightly related to the induction of the cyclin-dependent kinase inhibitors p21 and p27 . Notably, we further demonstrated that the up-regulation of p21 and p27 is transcriptionally dependent on the bortezomib-activated ER stress signalling branch Ire1α/Xbp1s. Taken together, these findings reveal an intracellular pathway that integrates proteasome inhibition, osteogenic differentiation and the cell cycle through activation of the ER stress signalling branch Ire1α/Xbp1s.
间充质干细胞（MSCs）是多能细胞，能够分化为多种细胞类型。硼替佐米，第一种被批准用于多发性骨髓瘤（MM）治疗的蛋白酶体抑制剂，已被证明能诱导成骨细胞分化，对骨髓瘤骨病有益。在本研究中，我们旨在研究硼替佐米在成骨分化过程中对细胞周期的影响及其潜在机制。我们证实低剂量的硼替佐米能诱导 MSC 向成骨分化，但高剂量则有毒性。在硼替佐米诱导的成骨分化过程中，我们观察到细胞周期退出，表现为 G1 期细胞周期阻滞，细胞增殖显著减少。此外，我们发现细胞周期退出与细胞周期蛋白依赖性激酶抑制剂 p21 和 p27 的诱导密切相关。值得注意的是，我们进一步证明了 p21 和 p27 的上调转录依赖于硼替佐米激活的内质网应激信号分支 Ire1α/Xbp1s。综上所述，这些发现揭示了一条通过激活内质网应激信号分支 Ire1α/Xbp1s 将蛋白酶体抑制、成骨分化和细胞周期整合在一起的细胞内途径。
