The USP14–NLRC5 pathway inhibits titanium particle–induced osteolysis in mice by suppressing NF-κB and PI3K/AKT activities

Abstract

Total hip arthroplasty (THA) is a widely-used surgical intervention for treating patients with end-stage degenerative and inflammatory osteoarthropathy. However, wear particles from the artificial titanium joint can induce osteolysis, limiting the long-term survivorship of THA. Monocyte/macrophage lineage cells are the key players in the response to wear particles, and the proinflammatory NF-κB and phosphoinositide 3-kinase (PI3K)–AKT Ser/Thr kinase (AKT)-signaling pathways have been shown to be the most important contributors to wear particle–induced osteolysis. In contrast, ubiquitin-specific protease 14 (USP14) specifically removes the polyubiquitin chains from the nucleotide-binding and oligomerization domain (NOD)-like receptor family Caspase recruitment domain (CARD)–containing 5 (NLRC5) and thereby enhances the NLRC5-mediated inhibition of NF-κB signaling. In this study, we aimed to clarify the role of the USP14–NLRC5 pathway in wear particle–induced osteolysis in vitro and in vivo. We found that NLRC5 or USP14 overexpression inhibits titanium particle–induced proinflammatory tumor necrosis factor α (TNFα) production and NF-κB pathway activation, and it also decreases M1 macrophage polarization and PI3K/AKT pathway activation. Of note, NLRC5 and USP14 overexpression attenuated titanium particle–induced cranial osteolysis in mice. In conclusion, the findings of our study indicate that the USP14–NLRC5 pathway inhibits titanium particle–induced osteolysis by suppressing the NF-κB and PI3K/AKT pathways both in vitro and in vivo.

USF1-ATRAP-PBX3 Axis Promote Breast Cancer Glycolysis and Malignant Phenotype by Activating AKT/mTOR Signaling

“…To elucidate the mechanism by which ATRAP interacts with and stabilizes PBX3 protein, we conducted co-immunoprecipitation assays followed by mass spectrometry to screen ATRAP-interacting proteins. Mass spectrometry data ( Table S5 ) indicated that the USP14, one of three proteasome-related deubiquitinating enzymes that can remove ubiquitin from the proteasome substrate before it is degraded 32 , was a strong candidate for further binding validation (Figure 4 J). We subsequently performed co-IP assays with a Flag-tagged ATRAP or USP14 antibody to validate whether ATRAP interacts with endogenous USP14.…”

STING/TBK1 Regulates Inflammation in Macrophages and Titanium Particles-Induced Osteolysis

“…Wear particles can be sensed by macrophages either in the free stage or when bound to carrier proteins. Receptors on the macrophage membrane [pattern-recognition receptors (PRRs)] or intracellular receptors [nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs)], when wear particles are phagocytosed, can be activated to deliver inflammatory signals, which is elucidated in our previous research studies. , Intracellular pathways, such as NF-κB and IRF3 and macrophages M1 polarization, are subsequently activated to initiate inflammatory responses. ,− In recent studies, TBK1, a member of unconventional IKK family, has been proved to be dimerized by STING, and the activation of TBK1 could further activate the NF-κB pathway by phosphorylating IκB proteins for degradation. − Therefore, we hypothesized that STING-modulated TBK1 may regulate TiPs-induced osteolysis.…”

BTK Promotes Atherosclerosis by Regulating Oxidative Stress, Mitochondrial Injury, and ER Stress of Macrophages

“…The experiments of immunofluorescent staining and confocal microscopy were performed essentially as described in Fang et al [ 44 ]. Shortly, macrophages were seeded in confocal dishes fixed with 4% paraformaldehyde after different treatments.…”