Circulating cellular senescence biomarkers in persons with chronic knee osteoarthritis pain: An exploratory study

The senescence-associated secretory phenotype (SASP) contributes to tissue degeneration and inflammation, yet its role in osteoarthritis (OA)-related pain remains poorly understood. We hypothesized that circulating SASP markers would be associated with distinct OA-pain phenotypes, defined by pain impact and radiographic OA (ROA) severity. A subset of middle-to-older-aged adults (45-85 years) from a larger multi-site study (n = 169) self-reported pain impact - defined as the extent to which pain interferes with daily functioning - and underwent knee radiography and blood collection. Hierarchical cluster analysis was used to empirically identify OA-pain phenotypes based on combined pain impact and Kellgren-Lawrence (KL) grade. Plasma levels of four SASP markers (GDF-15, activin-A, Osteopontin (OPN), and IL-15) were quantified from whole blood samples. Among 169 participants, 35.5% reported high-impact chronic knee pain and 27.8% exhibited moderate-to-severe radiographic OA. Cluster analysis identified distinct ROA-pain phenotypes. GDF-15 levels were significantly elevated in non-Hispanic White females with early ROA and high-impact pain, with race- and sex-dependent differences. Activin-A levels were higher in non-Hispanic Black participants without pain or ROA and varied by sex in early ROA/low-impact pain phenotypes. Osteopontin levels were elevated in males compared to females within the same phenotype group. IL-15 levels showed no association with ROA-pain phenotypes but were higher in males and positively correlated with age. SASP factors, particularly GDF-15, Activin-A, and Osteopontin, demonstrated race- and sex-dependent associations with OA-pain phenotypes. These findings underscore the importance of demographic context in OA pathophysiology and support further investigation into SASP factors as potential biomarkers and therapeutic targets for OA-related pain.