Abstract
Aseptic loosening is a major complication of prosthetic joint surgery, characterized by chronic inflammation, pain, and osteolysis surrounding the bone-implant interface. Progranulin (PGRN) is known to have anti-inflammatory action by binding to Tumor Necrosis Factor (TNF) receptors and antagonizing TNFα. Here we report that titanium particles significantly induced PGRN expression in RAW264.7 cells and also in a mouse air-pouch model of inflammation. PGRN-deficiency enhanced, whereas administration of recombinant PGRN effectively inhibited, titanium particle-induced inflammation in an air pouch model. In addition, PGRN also significantly inhibited titanium particle-induced osteoclastogenesis and calvarial osteolysis in vitro, ex vivo and in vivo. Mechanistic studies demonstrated that the inhibition of PGRN on titanium particle induced-inflammation is primarily via neutralizing the titanium particle-activated TNFα/NF-κB signaling pathway and this is evidenced by the suppression of particle-induced IκB phosphorylation, NF-κB p65 nuclear translocation, and activity of the NF-κB-specific reporter gene. Collectively, these findings not only demonstrate that PGRN plays an important role in inhibiting titanium particle-induced inflammation, but also provide a potential therapeutic agent for the prevention of wear debris-induced inflammation and osteolysis.
Highlights
Given the importance of the TNFα /nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κ B) signaling pathway in the pathogenesis of inflammatory osteolysis and PGRN’s anti-TNF activity, we hypothesized that PGRN might represent a novel treatment for titanium-induced inflammatory osteolysis
Total joint arthroplasty (TJA) is a common strategy in clinic for therapy of osteoarthritis, rheumatoid arthritis and other joint diseases[38]
Periprosthetic osteolysis followed by aseptic loosening still remains the major cause of TJA failure and frequently leads to revision surgery[30,43]
Summary
Given the importance of the TNFα /NF-κ B signaling pathway in the pathogenesis of inflammatory osteolysis and PGRN’s anti-TNF activity, we hypothesized that PGRN might represent a novel treatment for titanium-induced inflammatory osteolysis. We examined the expression pattern of PGRN following induction of titanium particle-induced inflammation both in vitro and in vivo, and determined the effects of endogenous and exogenous PGRN in titanium-induced inflammatory osteolysis as well as the signaling pathways involved
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