Int J Biol Sci 2021; 17(5):1382-1394. doi:10.7150/ijbs.53992

Research Paper

Inhibition of Sirtuin 3 prevents titanium particle-induced bone resorption and osteoclastsogenesis via suppressing ERK and JNK signaling

Ning Li1*, Xiaoping Li1*, Kai Zheng1*, Jiaxiang Bai1, Weicheng Zhang1, Houyi Sun1, Gaoran Ge1, Wei Wang1, Zhen Wang2, Ye Gu3, Yi Xue4, Yaozeng Xu1✉, Dechun Geng1✉, Jun Zhou1✉

1. Department of Orthopaedics, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou, Jiangsu 215006, China.
2. Department of Orthopaedics, Suzhou Kowloon Hospital Shanghai Jiao Tong University School of Medicine, Suzhou, Jiangsu 215006, China.
3. Department of Orthopedics, Soochow University Affiliated First People's, Hospital of Changshou City, Changshu, Jiangsu 215500, China.
4. Department of Orthopaedics, Changshu Hospital Affiliated to Nanjing University of Traditional Chinese Medicine, Suzhou, Jiangsu 215500, China.
*These authors contributed equally to this work.

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Citation:
Li N, Li X, Zheng K, Bai J, Zhang W, Sun H, Ge G, Wang W, Wang Z, Gu Y, Xue Y, Xu Y, Geng D, Zhou J. Inhibition of Sirtuin 3 prevents titanium particle-induced bone resorption and osteoclastsogenesis via suppressing ERK and JNK signaling. Int J Biol Sci 2021; 17(5):1382-1394. doi:10.7150/ijbs.53992. Available from https://www.ijbs.com/v17p1382.htm

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Abstract

Implant-derived wear particles can be phagocytosed by local macrophages, triggering an inflammatory cascade that can drive the activation and recruitment of osteoclasts, thereby inducing peri-prosthetic osteolysis. Efforts to suppress pro-inflammatory cytokine release and osteoclastsogenesis thus represent primary approaches to treating and preventing such osteolysis. Sirtuin 3 (SIRT3) is a NAD+-dependent deacetylases that control diverse metabolic processes. However, whether SIRT3 could mitigate wear debris-induced osteolysis has not been reported. Herein we explored the impact of the SIRT3 on titanium particle-induced osteolysis. Tartrate resistant acid phosphatase (TRAP) staining revealed that the inhibition of SIRT3 suppressed nuclear factor-κB ligand (RANKL)-mediated osteoclasts activation in a dose-dependent fashion. Notably, inhibition of SIRT3 also suppressed matrix metallopeptidase 9 (MMP9) and nuclear factor of activated T‐cell cytoplasmic 1 (NFATc1) expression at the mRNA and protein levels, while also inhibiting the mRNA expression of dendritic cell-specific transmembrane protein (DC-STAMP), ATPase H+ Transporting V0 Subunit D2 (Atp6v0d2), TRAP and Cathepsin K (CTSK) . In addition, inhibition of SIRT3 suppressed titanium particle-induced tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) expression and prevented titanium particle-induced osteolysis and bone loss in vivo. This inhibition of osteoclasts differentiation was found to be linked to the downregulation and reduced phosphorylation of JNK and ERK. Taken together, inhibition of SIRT3 may be a potential target for titanium particle-induced bone loss.

Keywords: Sirtuin 3, peri-prosthetic osteolysis, osteoclasts, inflammatory factors