Plasma levels and peripheral DNA methylation of IGF-1 and IGF-2 across knee osteoarthritis pain phenotypes in middle-aged and older adults.

Osteoarthritis (OA) is a leading cause of pain and disability, yet the biological mechanisms linking structural disease and pain remain incompletely understood. Insulin-like growth factors (IGFs) are involved in cartilage homeostasis, inflammation, and pain signaling and may serve as biomarkers or therapeutic targets in OA. This exploratory cross-sectional study examined associations between circulating levels and peripheral blood DNA methylation of IGF1 and IGF2 with chronic knee OA pain phenotypes in 158 adults aged 45-85 years with and without symptomatic knee OA. Participants were classified into five radiographic OA (ROA)-pain phenotypes based on pain impact and Kellgren-Lawrence grade: no pain/no ROA, pain/no ROA, pain/late ROA, high-impact pain/early ROA, and low-impact pain/early ROA. In adjusted analyses, ROA-pain phenotypes were associated with circulating IGF-1 and IGF-2 levels in a sex-dependent manner. Females with low-impact pain and early ROA had higher IGF-1 levels than males in the same phenotype. For IGF-2, males with no ROA, with and without pain, had higher levels than males with high-impact pain and early ROA, and males with no pain/no ROA also had higher IGF-2 levels than females. Mean DNA methylation levels of IGF1 and IGF2 showed limited associations after covariate adjustment, and no probe-level findings survived multiple-testing correction. These findings identify sex-dependent associations between circulating IGF-1 and IGF-2 and knee OA pain phenotypes, most notably lower IGF-2 in males with high-impact pain and early radiographic disease. The largely null peripheral methylation results suggest that tissue-level epigenetic regulation of IGF pathways, beyond what the buffy coat captures, warrants further investigation in larger cohorts.