Reactive oxygen and nitrogen species induce protein and DNA modifications driving arthrofibrosis following total knee arthroplasty.

Authors

Theresa A Freeman, Department of Orthopaedic Surgery, Thomas Jefferson UniversityFollow
Javad Parvizi, The Rothman Institute of Orthopedics at Thomas Jefferson UniversityFollow
Craig J Della Valle, Department of Orthopaedic Surgery, Rush University Medical CenterFollow
Marla J Steinbeck, Department of Biomedical Engineering and Department of Drexel Medicine, Drexel UniversityFollow

Document Type

Article

Publication Date

11-13-2009

Comments

This article has been peer reviewed and is published in Fibrogenesis & Tissue Repair 2009, 2:5. The published version is available at DOI: 10.1186/1755-1536-2-5. © BioMed Central

Abstract

BACKGROUND: Arthrofibrosis, occurring in 3%-4% of patients following total knee arthroplasty (TKA), is a challenging condition for which there is no defined cause. The hypothesis for this study was that disregulated production of reactive oxygen species (ROS) and nitrogen species (RNS) mediates matrix protein and DNA modifications, which result in excessive fibroblastic proliferation.

RESULTS: We found increased numbers of macrophages and lymphocytes, along with elevated amounts of myeloperoxidase (MPO) in arthrofibrotic tissues when compared to control tissues. MPO expression, an enzyme that generates ROS/RNS, is usually limited to neutrophils and some macrophages, but was found by immunohistochemistry to be expressed in both macrophages and fibroblasts in arthrofibrotic tissue. As direct measurement of ROS/RNS is not feasible, products including DNA hydroxylation (8-OHdG), and protein nitrosylation (nitrotyrosine) were measured by immunohistochemistry. Quantification of the staining showed that 8-OHdg was significantly increased in arthrofibrotic tissue. There was also a direct correlation between the intensity of inflammation and ROS/RNS to the amount of heterotopic ossification (HO). In order to investigate the aberrant expression of MPO, a real-time oxidative stress polymerase chain reaction array was performed on fibroblasts isolated from arthrofibrotic and control tissues. The results of this array confirmed the upregulation of MPO expression in arthrofibrotic fibroblasts and highlighted the downregulated expression of the antioxidants, superoxide dismutase1 and microsomal glutathione S-transferase 3, as well as the significant increase in thioredoxin reductase, a known promoter of cell proliferation, and polynucleotide kinase 3'-phosphatase, a key enzyme in the base excision repair pathway for oxidative DNA damage.

CONCLUSION: Based on our current findings, we suggest that ROS/RNS initiate and sustain the arthrofibrotic response driving aggressive fibroblast proliferation and subsequent HO.

Recommended Citation

Freeman, Theresa A; Parvizi, Javad; Della Valle, Craig J; and Steinbeck, Marla J, "Reactive oxygen and nitrogen species induce protein and DNA modifications driving arthrofibrosis following total knee arthroplasty." (2009). Department of Orthopaedic Surgery Faculty Papers. Paper 36.
https://jdc.jefferson.edu/orthofp/36

PubMed ID

19912645