Strontium inhibits titanium particle-induced osteoclast activation and chronic inflammation via suppression of NF-κB pathway.

Shijun Zhu,Xuanyang Hu,Yunxia Tao,Jiawei Shi,Yaozeng Xu,Xiexing Wu,Huilin Yang,Zichuan Ping,Zhikui Nie,Liangliang Wang,Zhirong Wang,Dechun Geng,Wen Zhang

doi:10.1038/srep36251

Abstract

Wear-particle-induced chronic inflammation and osteoclastogenesis have been identified as critical factors of aseptic loosening. Although strontium is known to be involved in osteoclast differentiation, its effect on particle-induced inflammatory osteolysis remains unclear. In this study, we investigate the potential impact and underling mechanism of strontium on particle-induced osteoclast activation and chronic inflammation in vivo and in vitro. As expected, strontium significantly inhibited titanium particle-induced inflammatory infiltration and prevented bone loss in a murine calvarial osteolysis model. Interestingly, the number of mature osteoclasts decreased after treatment with strontium in vivo, suggesting osteoclast formation might be inhibited by strontium. Additionally, low receptor activator of nuclear factor-κB ligand (RANKL), tumor necrosis factor-α, interleukin-1β, interleukin-6 and p65 immunochemistry staining were observed in strontium-treatment groups. In vitro, strontium obviously decreased osteoclast formation, osteoclastogenesis-related gene expression, osteoclastic bone resorption and pro-inflammatory cytokine expression in bone-marrow-derived macrophages in a dose-dependent manner. Furthermore, we demonstrated that strontium impaired osteoclastogenesis by blocking RANKL-induced activation of NF-κB pathway. In conclusion, our study demonstrated that strontium can significantly inhibit particle-induced osteoclast activation and inflammatory bone loss by disturbing the NF-κB pathway, and is an effective therapeutic agent for the treatment of wear particle-induced aseptic loosening.

Highlights

Cytokines, such as tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β)and IL-65,7,9,11,12
Binding of RANKL to RANK initiates the recruitment of TNF receptor-associated factor 6 and prompts induction of the nuclear factor-κB (NF-κB) pathway which induces osteoclastogenesis to result in the peri-prosthetic osteolysis[17,18,19]
In SrRan-treatment groups, particle-induced osteolysis was reduced in a dose-dependent manner, and bone resorption in mice treated with the high-SrRan concentration was much less than in mice treated with the low-SrRan concentration (Fig. 1A)

Summary

Introduction

Cytokines, such as tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β)and IL-65,7,9,11,12. In vitro data have demonstrated that strontium acts in part by decreasing osteoclast formation and bone resorption[21,22,23,24] It reduces the differentiation of osteoclasts by modulating the NF-κB pathway, as well as the number and activity of osteoclasts[23,24]. Strontium inhibits the expression of pro-inflammatory cytokines, such as TNF-αand IL-625 Since these factors play an important role in aseptic loosening, it’s reasonable to believe that strontium might be a good agent for treating aseptic loosening. Our data showed that strontium obviously inhibited titanium particle-induced inflammatory bone destruction and osteoclatogenesis through the suppression of NF-κB pathway. The results of this study provide a possible mechanistic explanation for the protective effect of strontium against wear-debris-induced osteolysis and provide a rationale for strontium use in the treatment of peri-prosthetic osteolysis and subsequent aseptic loosening

Objectives

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Results

Conclusion