Plasma Proteomics Identifies Pathways and Key Proteins Associated with Postoperative Joint Pain After Total Joint Arthroplasty in Osteoarthritis Patients

Objectives To identify molecular pathways and key proteins associated with postoperative joint pain following total joint arthroplasty (TJA) in osteoarthritis (OA) patients using a plasma proteomics approach. Methods Primary OA patients who underwent total knee or hip arthroplasty were assessed for their postoperative pain at least 1-year after surgery using the WOMAC Likert 3.0 pain subscale. Three pain phenotypes were defined: sustained pain (pain on all 5 questions), pain while active (pain while walking and taking stairs), and pain at rest (pain while sitting/lying and at night while in bed). Patients reporting no pain were classified as controls. Plasma proteomic profiling was performed using the Olink® Explore HT platform. Associations between postoperative joint pain and protein expression were assessed using logistic regression adjusted for age, sex, and body mass index. Functional enrichment analysis was conducted using KEGG and GO databases. Protein-protein interaction network was constructed using the STRING database and visualized in Cytoscape 3.10.4 to identify hub proteins. Bonferroni correction was applied to control for multiple testing across 5416 proteins and 3 pain phenotypes (α=3.08×10-6). Results A total of 149 patients were included. The prevalence of sustained pain, pain while active, and pain at rest 4 years after TJA was 5, 13, and 7%, respectively; 81% reported no pain, thereby served as controls (Figure 1A). No individual protein remained significant after multiple testing correction. However, 246, 332, and 260 proteins were nominally associated (p<0.05) with sustained pain, pain while active, and pain at rest, respectively. For sustained pain and pain at rest, the associated proteins were enriched in the MAPK signaling pathway, extracellular matrix, and growth factor activity. Hub proteins included CCL2, ERBB4, SHC1, NCAM1, MMP9, HRAS, FGF3, and NTRK2 for sustained pain, CD86, NCAM1, and ANXA5 for pain at rest (Figure 1B, 1D). Proteins associated with pain while active were enriched in the interleukin 17 signaling pathway, myeloid leukocyte mediated immunity, and cytokine activity. Hub proteins included ITGB2, CASP8, and CCL2 (Figure 1C). Figure 1. Conclusion Our data showed distinct molecular signatures for different postoperative pain phenotypes following TJA. While sustained and rest pain shared enrichment in MAPK-related and extracellular matrix pathways, pain while active appeared to involve immune and inflammatory mechanisms. These findings highlight potential protein biomarkers and pathways contributing to heterogeneous postoperative pain experience in OA patients.