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

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.

METTL3 Regulates Osteoclast Biological Behaviors via iNOS/NO-Mediated Mitochondrial Dysfunction in Inflammatory Conditions

“…Based on the inhibitory effects of METTL3 silencing on inflammatory osteoclast differentiation and bone resorption in vitro, further experiments were performed to explore the potential role of METTL3 in pathological bone loss in vivo. We constructed an LPS-induced cranial osteolysis mouse model, as previously described, and locally injected lentivirus-carrying shRNAs [ 56 , 57 ]. As evaluated through Micro-CT scanning, the injection of lentivirus-carrying Mettl3 -shRNA significantly suppressed LPS-induced osteolysis.…”

The potential role of herbal extract Wedelolactone for treating particle-induced osteolysis: an in vivo study

“…Studies have shown that some compounds from Chinese herbal medicines can treat particle-induced osteolysis by inhibiting the modules in the NF-κB signaling pathway, the main mechanism in the regulation of osteolysis, to effect the balance of osteoclasts and osteoblasts [ 12 , 45 , 50 , 61 , 68 ]. WDL is known for its ability to block the phosphorylation of IκBα, which acts to regulate the transcription of NF-κB mediated genes, inhibiting LPS-induced pro-inflammation [ 69 ].…”

“…As the ratio of RANKL/OPG increases, the osteoclast precursors are easier influenced by RANKL signaling through the downstream activation of NF-κB/c-fos/NFATc1, subsequently causing the precursors to differentiate into mature osteoclasts. On the other hand, macrophages also plays a key role in wear particle-induced osteolysis [63,[65][66][67][68]. Cytokines (TNF-α and IL-1β, etc.)…”

Macrophages in aseptic loosening: Characteristics, functions, and mechanisms

“…Therefore, IKK inhibitors reduce LPS-induced expressions of IL-1, IL-6, IL-10, TNF-a, and IFN (204). Recent studies have revealed that diverse wear particles (e.g., Ti, TiPs, HA, PE, PMMA) could induce the macrophage to release proinflammatory cytokines and chemokines, which are accomplished by the activation of NF-kB signaling pathways and associated macrophage polarization (15,26,54,205). Qiu et al found that stimulation of LPS or Ti particles could up-regulate p-IKKb, p-IkBa, and p-p65 and significantly increase the translocation of p65 into the nucleus in BMDMs.…”