CSPG4+ extracellular vesicles carry fibronectin and interleukin-11 and reflect radiographic severity in knee osteoarthritis.

OBJECTIVES: To evaluate chondroitin sulfate proteoglycan 4 (CSPG4)+ plasma extracellular vesicles (EVs) as a novel biomarker for knee osteoarthritis (OA) severity across independent study cohorts. METHODS: Radiographic and symptomatic OA severity were evaluated in participants from two separate institutions. EVs were isolated from plasma (discovery cohort, n = 51; validation cohort, n = 92) and synovial fluid (SF) (n = 61) from 204 OA patients and characterized by morphology, surface markers, and pathogenic cargo, and evaluated for associations with knee OA severity. Single-cell RNA sequencing datasets (GSE152805 and GSE216651) were used to elucidate the joint tissue localization of the genes of interest. RESULTS: Across both discovery and validation cohorts, plasma CSPG4+ EV frequencies showed positive correlations with knee radiographic OA severity scores, reflecting joint structural damage, but not with symptomatic OA severity. In OA joint tissues, particularly in damaged cartilage-derived chondrocytes, the CSPG4 gene was co-expressed with FN1 and IL11 genes, which encode the OA pathogenic mediators fibronectin (FN1) and interleukin-11 (IL-11). Consistent with this, OA SF CSPG4+ EVs carried higher proportions of FN1 and IL-11 compared with CSPG4- EVs, identifying these proteins as enriched pathogenic cargo of the CSPG4+ EV subset in OA. CONCLUSIONS: We identified CSPG4+ EV subpopulations in plasma as novel biomarkers of knee radiographic OA severity, reflecting underlying structural joint damage. In SF, CSPG4+ EVs were enriched in FN1 and IL-11, potent mediators of matrix remodeling and inflammatory signaling in OA, consistent with a role for CSPG4+ EV cargo in joint deterioration.

Duke Scholars

Author Virginia Byers Kraus Medicine, Rheumatology and Immunology

Author Xin Zhang Orthopaedic Surgery