The role of inflammation and oxidative stress in total hip replacement revisions
Authors:   , Jablonowski Lauren Jo , Allen Fred D. 
Published: July 2021

In the United States, the standard of care for degenerative joint disease is total joint replacement (TJR) with over 600,000 total hip and knee replacements performed each year. However, roughly 20% of these surgeries require a revision surgery as a result of tissue reactions to polyethylene wear debris. The reaction to wear debris stimulates an inflammatory response that initiates and promotes osteolysis, a progressive inflammatory-mediated bone resorptive disease. The goal of this study was to identify inflammatory and oxidative stress specific proteins and products involved in the development of osteolysis in revised total joint replacement tissues. Polarized light microscopy was used to determine the number of polyethylene particles embedded in total hip replacement (THR) revision tissues as a result of implant wear. Tissues from patients with increased amounts of osteolysis showed an average of 51.8 ± 36.8 particles per mm2 of tissue (Groups 1-3; increasing severity of osteolysis), while non-osteolytic tissues (control, Group 4) contained 1.5 ± 0.3 particles per mm2 of tissue. Inflammation was present in all osteolytic tissues, and to a lesser extent in control tissues. Immunohistochemistry was used to compare the severity of osteolysis with high mobility group protein B1 (HMGB1), reactive oxygen species (ROS) enzyme cyclooxygenase-2 (COX2), reactive nitrogen species (RNS) enzyme inducible nitric oxide synthase (iNOS), and their oxidized products 4-hydroxynonenal (4-HNE) and nitrotyrosine (Nitro, NT). Pearson's correlation coefficient and principle component analysis were performed. Results from the most severe osteolytic group (Group 1) showed significant correlations between increased vascularity and 4HNE, COX2, iNOS. Both severe and moderate osteolytic tissue groups (Groups 1 and 2) showed a strong correlation between particle number and HMBG1. Interestingly, patients in the low radiographic osteolysis group (Group 3) exhibited increased 4HNE and COX2, whereas this relationship was replaced by correlations of HMGB1 with iNOS in tissuesfrom patients with more severe osteolysis. The confirmed presence of ROS/RNS enzymes and products indicates oxidative stress is involved in the development of osteolysis. Building on the current findings, this study also includes the design of a genetic array and protein panel for the early diagnosis of THR osteolysis. The proposed designs are primarily based on the immunohistochemistry results, as well as review articles discussing genes associated with osteoclasts, osteoblasts and oxidative stress. The genes and proteins can be broken into five main categories: osteoclast-related, osteoblast-related, oxidative stress-related, inflammation-related, and controls. For the genetic array, 27 genes were selected for their involvement in osteoclast, osteoblast differentiation and function, as well the involvement of oxidative stress in osteolysis, along with 5 control elements. Similarly, for the protein panel, 28 proteins and oxidized products were selected for their involvement in osteoclast and osteoblast differentiation, oxidative stress, and osteolysis. Additionally, two protein controls were included for tissue or serum normalization of each factor. Serum samples will be collected from TJR patients using a standard blood collection protocol, and will be screened regularly for the presence of identified biomarkers in an attempt to obtain an early indication of osteolysis. Ultimately, the genetic array and protein panel for genes and proteins associated with oxidative stress could potentially be used for both early diagnosis and to identify potential therapeutic targets to treat osteolysis in TJR patients.