Protein misfolding in the synovium: the hidden face of osteoarthritis progression?

Most information on amyloid deposits occurring in joints with osteoarthritis (OA) focuses on cartilage and chondrocytes. The aim of this study was to investigate amyloid occurrence in OA synovium and the mechanisms underlying its deposition. Amyloid deposits in the synovium were investigated using sequence-independent and conformation-specific antibodies by immunohistochemistry (IHC) and western blot (WB). IHC and semiquantitative measurements were used to estimate amyloid amounts in ex vivo synovium specimens from OA patients and healthy donors and correlated with clinical features. Intrinsic misfolding was assessed by WB in primary synovial fibroblasts in control conditions or following proteostasis impairment (chloroquine, LPS). Fibrillar structure was confirmed by Transmission Electron Microscopy (TEM) analysis. All OA synovial specimens exhibited the presence of misfolded species whose distribution strongly suggests a circulating origin, as confirmed by IHC and TEM; this pattern was absent in healthy donors. Notably, misfolded species deposition correlated with synovitis severity, as assessed by the Krenn score ( p = 0.0036). Evidence of intrinsic deposition emerged in different cell types within the OA synovium. Proteostasis impairment in synoviocytes was confirmed by WB, suggesting basal inefficient autophagy and inadequate activity of the proteasome and chaperone systems. These findings extend current knowledge beyond superficial amyloid deposits in OA synovium correlating its deposition with inflammation. The involvement of impaired protein quality control mechanisms was demonstrated also in vitro, highlighting synovial involvement in OA pathophysiology and hinting at proteostasis impairment contribution in the disease and its rescue as a potential therapeutic strategy.