Sexual Dimorphism in Clinical Manifestations of Knee Osteoarthritis.

Abstract

While sexual dimorphism of knee osteoarthritis (KOA) is well established, sex-specific clinical manifestations-particularly involving periarticular tissues undetectable by radiography-remain underexplored. This study aimed to define female-specific alterations in joint integrity, periarticular muscle quality, symptom presentation, and the transcriptomic landscape of periarticular muscles, with the goal of uncovering the mechanistic contributions of each to KOA pathophysiology. Forty-nine participants (32 females, 17 males; Kellgren-Lawrence grade 1-2) underwent clinical assessment, including (1) quantitative ultrasound assessment of the vastus medialis and rectus femoris muscles; (2) magnetic resonance imaging to assess joint integrity; and (3) patient-reported outcomes. Principal component analysis followed by receiver operating characteristic curve analysis was conducted to identify discriminative sex-specific imaging and symptom features. Correlation-based network analysis examined sex-specific interdependencies among clinical variables. Publicly available transcriptomic datasets were analyzed to identify molecular drivers underlying female-specific muscle quality changes. Despite similar radiographic severity and symptom presentation across the sexes, female individuals exhibited greater cartilage degeneration and higher fatty infiltration in the vastus medialis and rectus femoris. These features were central to sex separation in the principal component analysis, with both features identified as network hubs in female individuals, indicating interconnected muscle-joint degeneration. Transcriptomic analysis revealed enrichment of adipogenic reprogramming in female individuals, suggesting aberrant intramuscular fat programming. Our findings uncover a distinct female-specific musculoskeletal phenotype in early-stage KOA, characterized by muscle degeneration and cartilage deterioration undetectable by radiography. These female-specific clinical manifestations may be due, at least partly, to aberrant adipogenic programming in muscle. These findings provide mechanistic and clinical insight into sexual dimorphism in KOA.