Denosumab Regulates Titanium Particles-Induced Macrophages Inflammation and Osteolysis by Targeting the ST18/PARP1...

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.