Spatial Proteomics Identifies Distinct Synovial Microenvironments in Hip and Knee Osteoarthritis

Objective Osteoarthritis (OA) is a heterogeneous joint disease, yet mechanistic insights derive predominantly from knee OA and are often extrapolated to other joints. We investigated joint‐associated differences in the spatial molecular organization of hip and knee OA synovium. Methods Synovial tissues from patients undergoing arthroplasty for primary hip or knee OA were analyzed by histology ( hip, n=10; knee, n=10 ), mass spectrometry–based bulk proteomics ( hip, n=10; knee, n=8 ), and NanoString GeoMx Digital Spatial Profiling ( hip, n=5; knee, n=5 ). Spatial proteomic profiling was performed across intimal and subintimal regions segmented into CD45 + immune and CD45 ‐ non‐immune compartments. Results Hip OA synovium exhibited greater vessel density than knee OA synovium ( P < 0.001 ), whereas histological synovitis severity did not differ significantly. Bulk proteomics showed enrichment of angiogenesis in hip OA ( FDR q=0.001 ) and fatty acid metabolism in knee OA ( FDR q<0.001 ). Spatial proteomic profiling revealed a vascular–stromal remodeling signature in the hip OA subintimal CD45 ‐ compartment, with higher abundance of VEGFR2, vWF, α‐SMA, PDGFB, and YAP1. Hip OA also showed higher CD3E/CD3G abundance in the subintimal CD45 + compartment and higher calreticulin abundance across multiple compartments. In contrast, knee OA exhibited a GLP‐1/GLP‐1R–associated metabolic signature in the intimal CD45 + compartment. The knee OA subintimal CD45 ‐ compartment also showed higher HK2 abundance and enrichment of lipid‐associated LXR/RXR signaling. Conclusion Hip and knee OA synovium exhibit distinct spatially organized molecular phenotypes, highlighting the importance of joint‐specific context in OA pathobiology. image