Distinct late-stage osteoarthritis profiles identified through NF-κB, TNF-α, and TGF-β-driven synovial inflammation and pain.

This study delineates distinct late-stage osteoarthritis (OA) profiles, characterized by NF-κB, TNF-α, and TGF-β-mediated synovial inflammation and pain, in a cohort of 31 patients undergoing joint arthroplasty. Histopathological analysis demonstrated synoviocyte hyperplasia, increased stromal cellularity, inflammatory infiltrates, and enhanced vascularization, findings that correlated with higher synovitis scores and exacerbated movement-associated nociception. Increased expression of NF-κB and TNF-α in the synovial membrane confirmed their association with stronger inflammation and pain perception. Bayesian networks revealed relationships among NF-κB, TNF-α, and pain scores, suggesting that NFκB is a primary driver of pain in low-grade synovitis, while TNF-α becomes more influential in high-grade synovitis. Cluster analysis identified four distinct patient subgroups: (1) males with severe radiographic OA, elevated NF-κB in both the synovium and fluid, and the absence of synovitis; (2) predominantly females with metabolic comorbidities, a variable degree of synovitis, and elevated TNF-α in synovial fluid; (3) patients with low pain scores and no histopathologically confirmed synovial inflammation; and (4) patients with high-grade synovitis, pronounced tissue alterations, increased NF-κB, TNF-α, and TGF-β expression in the synovial membrane, but without metabolic comorbidities. The findings clarify the influence of synovitis in late-stage OA and suggest that the identified profiles may assist in earlier disease stratification and the development of tailored treatments in the future.