Icariin Alleviates Wear Particle-Induced Periprosthetic Osteolysis via Down-Regulation of the Estrogen Receptor α-mediated NF-κB Signaling Pathway in Macrophages.

Fu Guangtao,Chen Yuanfeng,Wen Zhenkang,Deng Zhantao,Zheng Qiujian,Li Mengyuan,Ma Yuanchen,Li Qingtian

doi:10.3389/fphar.2021.746391

Abstract

Periprosthetic osteolysis is one of the major long-term complications following total joint replacement. Its cause is widely accepted to be wear particle-induced activation of inflammatory macrophages. No effective strategy for the prevention and treatment of periprosthetic osteolysis is yet available. Recently, considerable evidence has shown that icariin effectively protects against estrogen deficiency-related bone loss and bone deterioration. However, the molecular mechanism underlying the inhibitory effect of icariin on wear particle-induced periprosthetic osteolysis is not yet clear. In this study, nanoscale CoCrMo wear particles were obtained by high-vacuum three-electrode direct current from the femoral head implant of a patient diagnosed with aseptic loosening. The effects of icariin on wear particle-induced expression of proinflammatory factors, NF-κB signaling modulation, osteolysis, and estrogen receptor α (ERα) activation were evaluated in vitro and in vivo using bone marrow-derived macrophages and C57/BL6J mice, respectively. A possible link between ERα and the protective effect of icariin was further studied using an ERα antagonist and the ERα-siRNA interference. Chemical composition analysis showed that Cr and Co were the major metallic elements of the nanoscale particles, with a mean size of 150.2 ± 37.4 nm for the CoCrMo particles. Following icariin treatment, significant decreases were observed in CoCrMo wear particle-induced TNF-α and IL-6 mRNA expression in BMDMs, and osteolysis in mice calvaria. Marked decreases in the protein expression level of p-IKKβ, p-p65 and p-IκBα were also observed, together with significant decreases in the nuclear import of P65 and macrophage M1 polarization. RNA sequencing revealed that ERα was closely associated with TNF-α and IL-6 in wear particle-stimulated macrophages. Furthermore, marked increases in phospho-ERα Ser118 and phospho-ERα Ser167 protein expression and the nuclear import of ERα were also found in the icariin group. The protective effects of icariin on CoCrMo particle-induced mouse calvarial osteolysis and on the inflammation response in BMDMs were reversed by ERα antagonist and by ERα-siRNA interference. In conclusion, icariin attenuates wear particle-induced inflammation and osteolysis via down-regulation of the ERα-mediated NF-κB signaling pathway in macrophages. The potential application of icariin as a non-hormonal therapy for wear particle-induced periprosthetic osteolysis is worthy of further investigation.

Highlights

Periprosthetic osteolysis is one of the major long-term complications following total joint replacement and is associated with aseptic implant failure and severely impaired joint function (Goodman et al, 2020)
Marked wear particle infiltration was found in hematoxylin and eosin (H&E)-stained sections of the synovial membranes obtained from the involved hip of patients diagnosed with aseptic loosening (Figure 2A)
Compared to the CoCrMo group, the CoCrMo + ICA group showed significantly lower TNF-α and IL-6 mRNA levels and protein secretion at 4, 8, 12 and 24 h after CoCrMo particle stimulation (Figure 3C). These results suggest that the inhibitory effect of ICA on the CoCrMo wear particle-induced macrophage inflammatory response was related to the downregulation of NF-κB signaling pathways

Summary

Introduction

Periprosthetic osteolysis is one of the major long-term complications following total joint replacement and is associated with aseptic implant failure and severely impaired joint function (Goodman et al, 2020). The pattern recognition receptor on the macrophage membrane and the downstream protein kinase cascade signaling pathways (MAPK, PI3k/Akt/NF-κB, etc.) are heavily involved in wear particle-induced chronic inflammatory and periprosthetic osteolysis (Goodman et al, 2020). These have been proposed as potential targets for novel medical therapies (Hu et al, 2020). There is currently no effective medical therapy for the prevention and treatment of periprosthetic osteolysis

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