Objectively evaluated joint function and patient-reported pain are associated with differences in the proteomic landscape of knee osteoarthritis

Knee osteoarthritis (KOA) is a multifactorial disease where the precise underlying cause is not fully understood. There may be individual factors that can influence progression and disease severity. Therefore, a better understanding of the functional and molecular changes that occur during KOA progression is essential. Identifying KOA-specific biomarkers associated with joint function and patient-reported outcomes may provide means for early interventions and could be used to subtype KOA to individualize treatments (1). Are there associations between objectively evaluated joint function, pain and KOA-specific biomarkers? Thirteen individuals with physician-diagnosed KOA and eleven age-matched healthy controls were included in this pilot study. All participants performed the 30 s Single Leg Mini Squat (SLMS) test and 30 s Sit-to-Stand test with simultaneous recording of joint kinematics using seven inertial measurement units (Opal, APDM). Individuals with KOA completed the patient-reported outcomes Forgotten Joint Score-12 (FJS) (2), and Knee Injury and Osteoarthritis Outcome Score (KOOS) (3). In blood plasma samples, SureQuant quantitative Mass Spectrometry (MS) was used to identify 500 differentially expressed proteins (DEPs) in KOA compared to controls (4). Principal component analysis (PCA), hierarchical cluster analysis (HCA), and Reactome enrichment analysis of the proteome were conducted to identify groups. Comparisons between groups were performed by using Student t-test. Correlations between clinical measures and MS data were explored using Spearman’s Rho. Individuals with KOA displayed worse clinical outcomes compared to controls. Performance-based function, as measured by the number of SLMS (Fig. 1A) and sit-to-stand repetitions (22 vs 33, 33%; 13 vs 21, 38%), was lower in individuals with KOA compared to controls. MS analysis identified 392 (of 500) proteins across all individuals. In total, we found 83 DEPs, where 25 were up-regulated and 58 down-regulated in KOA. PCA displayed distinct features between KOA and controls (Fig. 1B), similar to HCA, which distinguished two major clusters with some overlap. Twelve DEPs were associated with joint function, and seven DEPs were associated with pain outcomes. Interestingly, SLMS average range of motion displayed a moderate negative correlation to a bone resorption marker (CAH2) (Fig. 1C), and FJS and KOOS pain domain correlated with markers of platelet degranulation (HBD, HBB, ISLR), and the redox regulator PRDX2, indicated in inflammation. Fig. 1 A-1C.Download : Download high-res image (93KB)Download : Download full-size image We have examined the proteomic landscape of KOA and identified specific proteins related to joint function and pain. The findings of this pilot study show that joint function and pain may be associated with specific serological biomarkers of bone resorption, platelet degranulation, and inflammation. Further exploration of the protein characteristics and associations with joint function and pain may provide novel biomarkers and specific functional proteins that can be used for targeted KOA treatment.