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

J Biol Chem. 2020 May 15;295(20):7018-7032. doi: 10.1074/jbc.RA119.012495. Epub 2020 Apr 9.


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.

Keywords: NF-κB; NLRC5; USP14; cytokine; macrophage; osteoclast; total hip arthroplasty; tumor necrosis factor (TNF); wear particles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Hip Prosthesis / adverse effects
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Macrophages* / metabolism
  • Macrophages* / pathology
  • Mice
  • NF-kappa B / metabolism
  • Osteolysis* / chemically induced
  • Osteolysis* / metabolism
  • Osteolysis* / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects*
  • Skull* / metabolism
  • Skull* / pathology
  • Titanium / toxicity*
  • Tumor Necrosis Factor-alpha / metabolism
  • Ubiquitin Thiolesterase / metabolism*


  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • NLRC5 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Usp14 protein, mouse
  • Titanium
  • Proto-Oncogene Proteins c-akt
  • Ubiquitin Thiolesterase