Molecular Mechanism Underlying the Action of a Celastrol-Loaded Layered Double Hydroxide-Coated Magnesium Alloy in Osteosarcoma Inhibition and Bone Regeneration

作者：Cheng, Shi; Shao, Hongwei; Yin, Dong; Zhou, Jielong; Jian, Linjia; Xie, Juning; Zhang, Yu^*; Wang, Donghui^*; Peng, Feng^*

来源：ACS Biomaterials Science & Engineering, 2023, 9(8): 4940-4952.

DOI：10.1021/acsbiomaterials.3c00357

• osteosarcoma therapy
• magnesium alloy
• celastrol
• tumor suppression
• bone regeneration

Osteosarcoma (OS) is a malignant bone tumor that threatenshumanhealth. Surgical removal of the tumor and followed by implantationwith a graft is the golden standard for its clinical treatment. However,avoiding recurrence by enhancing the antitumor properties of the implantsand improving osteogenesis around the implants remain a challenge.Here, we developed a layered double hydroxide (LDH)-coated magnesium(Mg) alloy and loaded it with celastrol. The celastrol-loaded Mg alloyexhibited enhanced corrosion resistance and sustained release of celastrol. In vitro cell culture suggested that the modified Mg alloyloaded with an appropriate amount of celastrol significantly inhibitedthe proliferation and migration of bone tumor cells while having littleinfluence on normal cells. A mechanistic study revealed that the celastrol-loadedMg alloy upregulated reactive oxygen species (ROS) generation in bonetumor cells, resulting in mitochondrial dysfunction due to reducedmembrane potential, thereby inducing bone tumor cell apoptosis. Furthermore,it was found that celastrol-induced autophagy in tumor cells inhibitedcell apoptosis in the initial 6 h. After & GE;12 h of culture,inhibition of the PI3K-Akt-mTOR signaling pathway was noted, resultingin excessive autophagy in tumor cells, finally causing cell apoptosis.The celatsrol-loaded Mg alloy also exhibited effective antitumor propertiesin a subcutaneous tumor model. In vitro tartrate-resistantacid phosphatase (TRAP) staining and gene expression results revealedthat the modified Mg alloy reduced the viability of osteoclasts, inducinga potential pathway for the increased bone regeneration around themodified Mg alloy seen in vivo. Together, the resultsof our study show that the celatsrol-loaded Mg alloy might be a promisingimplant for treating OS.

• 单位
  南方医科大学; 广东省人民医院; y