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.