Inhibition of PAD4 mediated neutrophil extracellular traps prevents fibrotic osseointegration failure in a tibial implant murine model : an animal study.

TitleInhibition of PAD4 mediated neutrophil extracellular traps prevents fibrotic osseointegration failure in a tibial implant murine model : an animal study.
Publication TypeJournal Article
Year of Publication2021
AuthorsKuyl E-V, Shu F, Sosa BR, Lopez JD, Qin D, Pannellini T, Ivashkiv LB, Greenblatt MB, Bostrom MPG, Yang X
JournalBone Joint J
Issue7 Supple B
Date Published2021 Jul
KeywordsAnimals, Bone-Implant Interface, Deoxyribonuclease I, Disease Models, Animal, Extracellular Traps, Fibrosis, Mice, Mice, Inbred C57BL, Neutrophils, Osseointegration, Prosthesis Failure, Protein-Arginine Deiminase Type 4, Tibia

AIMS: Aseptic loosening is a leading cause of uncemented arthroplasty failure, often accompanied by fibrotic tissue at the bone-implant interface. A biological target, neutrophil extracellular traps (NETs), was investigated as a crucial connection between the innate immune system's response to injury, fibrotic tissue development, and proper bone healing. Prevalence of NETs in peri-implant fibrotic tissue from aseptic loosening patients was assessed. A murine model of osseointegration failure was used to test the hypothesis that inhibition (through mice that display defects in peptidyl arginine deiminase 4 (PAD4), an essential protein required for NETs) or resolution (via DNase 1 treatment, an enzyme that degrades the cytotoxic DNA matrix) of NETs can prevent osseointegration failure and formation of peri-implant fibrotic tissue.

METHODS: Patient peri-implant fibrotic tissue was analyzed for NETs biomarkers. To enhance osseointegration in loose implant conditions, an innate immune system pathway (NETs) was either inhibited ( mice) or resolved with a pharmacological agent (DNase 1) in a murine model of osseointegration failure.

RESULTS: NETs biomarkers were identified in peri-implant fibrotic tissue collected from aseptic loosening patients and at the bone-implant interface in a murine model of osseointegration failure. Inhibition ( ) or resolution (DNase 1) of NETs improved osseointegration and reduced fibrotic tissue despite loose implant conditions in mice.

CONCLUSION: This study identifies a biological target (NETs) for potential noninvasive treatments of aseptic loosening by discovering a novel connection between the innate immune system and post-injury bone remodelling caused by implant loosening. By inhibiting or resolving NETs in an osseointegration failure murine model, fibrotic tissue encapsulation around an implant is reduced and osseointegration is enhanced, despite loose implant conditions. Cite this article:  2021;103-B(7 Supple B):135-144.

Alternate JournalBone Joint J
PubMed ID34192911
Grant ListUL1 TR000457 / TR / NCATS NIH HHS / United States
Related Faculty: 
Matthew B. Greenblatt, M.D., Ph.D.

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