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Three-Dimensional Bone Extracellular Matrix Model for Osteosarcoma
Published on: April 12, 2019
Molecular Mechanism Underlying the Action of a Celastrol-Loaded Layered Double Hydroxide-Coated Magnesium Alloy in
Shi Cheng1,2, Hongwei Shao1, Dong Yin1
1Medical Research Institute, Department of Orthopedics, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
Abstract:
Osteosarcoma (OS) is a malignant bone tumor that threatens human health. Surgical removal of the tumor and followed by implantation with a graft is the golden standard for its clinical treatment. However, avoiding recurrence by enhancing the antitumor properties of the implants and 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 alloy exhibited enhanced corrosion resistance and sustained release of celastrol. In vitro cell culture suggested that the modified Mg alloy loaded with an appropriate amount of celastrol significantly inhibited the proliferation and migration of bone tumor cells while having little influence on normal cells. A mechanistic study revealed that the celastrol-loaded Mg alloy upregulated reactive oxygen species (ROS) generation in bone tumor cells, resulting in mitochondrial dysfunction due to reduced membrane potential, thereby inducing bone tumor cell apoptosis. Furthermore, it was found that celastrol-induced autophagy in tumor cells inhibited cell apoptosis in the initial 6 h. After ≥12 h of culture, inhibition of the PI3K-Akt-mTOR signaling pathway was noted, resulting in excessive autophagy in tumor cells, finally causing cell apoptosis. The celatsrol-loaded Mg alloy also exhibited effective antitumor properties in a subcutaneous tumor model. In vitro tartrate-resistant acid phosphatase (TRAP) staining and gene expression results revealed that the modified Mg alloy reduced the viability of osteoclasts, inducing a potential pathway for the increased bone regeneration around the modified Mg alloy seen in vivo. Together, the results of our study show that the celatsrol-loaded Mg alloy might be a promising implant for treating OS.
Insights
This study introduces a novel celastrol-loaded magnesium alloy implant coated with layered double hydroxide (LDH) to combat osteosarcoma (OS). The implant shows promise in inhibiting tumor cells and promoting bone regeneration, offering a new treatment strategy for OS.
Area of Science:
- Biomaterials Science
- Orthopedic Oncology
- Nanotechnology
Background:
- Osteosarcoma (OS) is a prevalent bone malignancy requiring effective clinical treatments.
- Current treatments face challenges in preventing tumor recurrence and enhancing bone regeneration post-surgery.
- Magnesium (Mg) alloys are promising for orthopedic implants due to their biodegradability, but require surface modification for enhanced functionality.
Purpose of the Study:
- To develop a layered double hydroxide (LDH)-coated magnesium (Mg) alloy loaded with celastrol for enhanced osteosarcoma treatment.
- To evaluate the implant's antitumor properties, biocompatibility, and osteogenic potential.
- To elucidate the underlying mechanisms of celastrol-induced apoptosis and autophagy in OS cells.
Main Methods:
- Fabrication of LDH-coated Mg alloy loaded with celastrol.
- In vitro assessment of cytotoxicity, anti-proliferative, and anti-migratory effects on OS cells and normal cells.
- Mechanistic studies involving reactive oxygen species (ROS) generation, mitochondrial dysfunction, and PI3K-Akt-mTOR pathway analysis.
- In vivo evaluation in a subcutaneous tumor model and in vitro tartrate-resistant acid phosphatase (TRAP) staining for osteoclast activity.
- Assessment of bone regeneration potential around the implant.
Main Results:
- The celastrol-loaded Mg alloy demonstrated enhanced corrosion resistance and sustained celastrol release.
- In vitro studies showed significant inhibition of OS cell proliferation and migration with minimal impact on normal cells.
- Celastrol induced OS cell apoptosis via ROS generation, mitochondrial dysfunction, and modulation of autophagy through the PI3K-Akt-mTOR pathway.
- The implant exhibited antitumor efficacy in vivo and reduced osteoclast viability, suggesting enhanced bone regeneration.
- In vitro TRAP staining and gene expression indicated reduced osteoclast activity.
Conclusions:
- The celastrol-loaded LDH-coated Mg alloy is a promising biomaterial for osteosarcoma treatment.
- The implant effectively inhibits OS progression and promotes bone regeneration.
- This novel implant offers a potential therapeutic strategy to overcome limitations in current OS clinical management.
