Movement smoothness and plasma proteomics are associated with functional impairment in knee osteoarthritis

Objective: To evaluate clinical outcomes (performance-based tests and patient-reported outcome measures [PROMs]) and biomechanical measures of movement smoothness, and explore their associations with molecular markers in individuals with knee osteoarthritis (KOA). Method: Thirty-six individuals with KOA (mean age 62.7 years; 75% female) and 19 controls (mean age 62.3 years; 63% female) performed four functional tests: 10 m Fast-Paced Walk (10MWT), 30 s Sit-to-Stand (30STS), Single Leg Mini Squat (SLMS), and Jump for Distance. Movement smoothness during 30STS and SLMS was quantified using Spectral Arc Length (SPARC) from inertial sensors. Individuals with KOA completed PROMs, and pain was assessed in both groups. Proteomic profiling (Olink) identified differentially expressed proteins (DEPs). Results: Individuals with KOA showed poorer performance across all functional tests (p < 0.001-0.04) and higher pain (p < 0.001). SPARC metrics indicated reduced movement smoothness, with lower mean SPARC (p < 0.001-0.004) and higher variance (p < 0.001). Nine DEPs distinguished the KOA group: one upregulated (DEFB4A) and eight downregulated (FKBP5, CETN2, TBCB, AXIN1, PMVK, PTPN1, PRTFDC1, ST1A1). All downregulated proteins correlated positively with 30STS performance (|r| = 0.37-0.57), and three negatively with 10MWT (|r| = 0.36-0.40). Higher mean SPARC during 30STS correlated positively with these proteins and partially during SLMS. PROMs showed moderate associations with functional outcomes. Conclusion: Individuals with KOA exhibited impaired function, reduced movement smoothness, and distinct proteomic profiles. Associations between proteins and movement quality suggest a molecular link to neuromuscular function. Combining proteomics with objective movement analysis and PROMs may improve understanding of KOA heterogeneity and support patient stratification.