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Published on: February 17, 2018
Denosumab Regulates Titanium Particles-Induced Macrophages Inflammation and Osteolysis by Targeting the ST18/PARP1
Zhipeng Chen1, Fan Yang1, Yifan Yu1
1Department of Orthopedic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Objective:
This study aims to investigate the role of Denosumab and its downstream target ST18 in wear particle-induced macrophage inflammation and osteolysis, and to explore the underlying mechanisms involved in aseptic loosening (AL) of prosthetic joints.
Methods:
Macrophages were stimulated with titanium particles (TiPs), and inflammatory responses were assessed using qRT-PCR, western blot, flow cytometry, and immunohistochemistry. Denosumab's effects on inflammation and osteolysis were evaluated with the same approaches. Potential targets of Denosumab were screened via online databases and validated by qRT-PCR and western blot. ST18 was modulated in macrophages using lentiviral overexpression and knockdown systems. A mouse calvarial model of TiPs-induced osteolysis was established, and the roles of Denosumab and ST18 were examined in vivo using micro-CT, H&E staining, and tartrate-resistant acid phosphatase (TRACP) staining.
Results:
Denosumab suppressed TiPs-induced macrophage inflammation by inhibiting NF-κB signaling and M1 polarization. We identified ST18 as a direct target of Denosumab, whose expression was upregulated by TiPs but downregulated by Denosumab. Lentivirus-mediated ST18 knockdown markedly attenuated TiPs-induced inflammation, whereas ST18 overexpression exacerbated it. Further analysis revealed that ST18 interacts with PARP1. In vivo, Denosumab significantly alleviated TiPs-induced osteolysis in mouse calvaria, an effect that was reversed by ST18 overexpression.
Conclusion:
Denosumab attenuates TiPs-induced macrophage activation and osteolysis through suppression of the NF-κB pathway and M1 polarization, with ST18 serving as a key mediator. These findings highlight Denosumab as a promising therapeutic candidate for the prevention of prosthesis-related aseptic loosening.
Insights
Denosumab reduces inflammation and bone loss caused by prosthetic joint wear particles by targeting ST18. This study reveals Denosumab
Area of Science:
- Biomedical Engineering
- Immunology
- Orthopedics
Background:
- Aseptic loosening (AL) is a major cause of prosthetic joint failure.
- Wear particles from implants trigger macrophage inflammation and osteolysis, contributing to AL.
- Understanding the molecular mechanisms of AL is crucial for developing effective treatments.
Purpose of the Study:
- To investigate Denosumab's role in wear particle-induced macrophage inflammation and osteolysis.
- To identify downstream targets of Denosumab, specifically ST18, in the context of AL.
- To elucidate the mechanisms underlying Denosumab's effects on aseptic loosening.
Main Methods:
- Macrophages were stimulated with titanium particles (TiPs) and analyzed for inflammatory responses.
- Denosumab's effects on inflammation and osteolysis were assessed in vitro and in vivo.
- ST18 was identified as a Denosumab target and its role investigated using overexpression and knockdown systems.
- A mouse calvarial model was used to evaluate Denosumab and ST18 in TiPs-induced osteolysis.
Main Results:
- Denosumab suppressed TiPs-induced macrophage inflammation by inhibiting NF-κB signaling and M1 polarization.
- ST18 was identified as a direct target of Denosumab, upregulated by TiPs and downregulated by Denosumab.
- ST18 knockdown attenuated TiPs-induced inflammation, while overexpression exacerbated it; ST18 interacts with PARP1.
- Denosumab alleviated TiPs-induced osteolysis in vivo, an effect reversed by ST18 overexpression.
Conclusions:
- Denosumab attenuates wear particle-induced macrophage activation and osteolysis via NF-κB pathway and M1 polarization suppression.
- ST18 acts as a key mediator in Denosumab's therapeutic effects against aseptic loosening.
- Denosumab shows promise as a therapeutic agent to prevent prosthesis-related aseptic loosening.
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