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

Abstract

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.