Surgical site peptidylarginine deaminase 4 (PAD4), a biomarker of NETosis, correlates with insulin resistance in total joint arthroplasty patients: A preliminary report

• Published in: PloS one Vol. 16; no. 1; p. e0245594
• Main Authors: Martins, Vitor F, Dobson, Christopher R, Begur, Maedha, Parekh, Jesal, Ball, Scott T, Gonzalez, Francis, Hughes-Austin, Jan M, Schenk, Simon
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2021; Public Library of Science (PLoS)
• Subjects: Adipose tissue; Arthritis; Arthroplasty; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Biological markers; Biology and Life Sciences; Biomarkers; Biomarkers - metabolism; Biomedical materials; Bone surgery; Causes of; Complications and side effects; Deoxyribonucleic acid; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diagnosis; DNA; Enzymes; Extracellular Traps - metabolism; Female; Glucose; Health aspects; Humans; Hyperglycemia; Immune response; Infections; Insulin; Insulin Resistance; Joint surgery; Joints (anatomy); Leukocytes (neutrophilic); Male; Medicine and Health Sciences; Methodology; Middle Aged; Muscle, Skeletal - pathology; Musculoskeletal system; Neutrophils; Nitrogen; Obesity; Orthopedics; Pathophysiology; Plasma; Priming; Protein-Arginine Deiminase Type 4 - metabolism; Risk factors; Sequestering; Surgeons; Surgery; Surgical implants; Surgical wound infections; Wound healing; Wound infection; United States; La Jolla California; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0245594

While obesity and insulin resistance are known risk factors for wound complications after total joint arthroplasty (TJA), the biologic causes remain to be elucidated. Recently, neutrophil extracellular trap formation (NETosis) was identified as a mediator of delayed wound healing in insulin resistant states. Herein, we explored the relationship between obesity, insulin resistance and biomarkers of NET formation in TJA subjects. We enrolled 14 obese (body mass index [BMI]≥30 kg/m2), and 15 lean (BMI<30 kg/m2) subjects undergoing primary knee or hip TJA. On the day of surgery, skeletal muscle proximal to the operated joint and plasma were collected. Protein abundance of NETosis biomarkers, peptidylarginine deaminase 4 (PAD4) and neutrophil elastase (NE) were assessed in skeletal muscle by immunoblotting and metabolic parameters (glucose, insulin, triglycerides, free fatty acids) and cell-free double-stranded DNA (cf-dsDNA) were assessed in plasma and were correlated with obesity and insulin resistance (as measured by the homeostatic model assessment for insulin resistance). When comparing lean and obese subjects, there were no significant differences in plasma cf-dsDNA or skeletal muscle NE or PAD4 abundance. In contrast, skeletal muscle PAD4 abundance, but not NE or plasma cf-dsDNA, was positively correlated with insulin resistance. Compared to insulin sensitive subjects, insulin resistant TJA subjects have higher expression of PAD4 at the surgical site and therefore may have higher rates of NET formation, which may lead to delayed surgical site wound healing.