title: Progranulin suppresses titanium particle induced inflammatory osteolysis by targeting TNFα signaling.
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.
authors: Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003, USA.|Department of Orthopaedic Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China.
authors: Yun-peng
authors: YP
authors: Zhao
authors: Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003, USA.|Department of Orthopaedic Surgery, Medical School of Shandong University, Jinan, Shandong, China.
authors: Jian-lu
authors: JL
authors: Wei
authors: Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003, USA.
authors: Qing-yun
authors: QY
authors: Tian
authors: Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003, USA.
authors: Alexander Tianxing
authors: AT
authors: Liu
authors: Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003, USA.
authors: Young-su
authors: YS
authors: Yi
authors: Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003, USA.
authors: Thomas A
authors: TA
authors: Einhorn
authors: Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003, USA.|Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
authors: Chuan-ju
authors: CJ
authors: Liu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D015870:Gene Expression; D000077155:Granulins; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007249:Inflammation; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D010014:Osteolysis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010316:Particle Size; D010766:Phosphorylation; D000077153:Progranulins; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D012886:Skull / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014025:Titanium / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D053245:RANK Ligand; C498144:Rela protein, mouse; C505689:Tnfsf11 protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D014025:Titanium; D051550:I-kappa B Kinase