Lysyl oxidase exacerbates rheumatoid arthritis through promoting angiogenesis and the proliferation of fibroblast-like synoviocytes.

Abstract

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by synovial hyperplasia and pannus formation, which serves as its primary pathological feature and may ultimately result in joint deformities. Lysyl oxidase (LOX) is involved in the formation and remodeling of the extracellular matrix, but its role in RA is not yet clear. This study aims to investigate the mechanism of lysyl oxidase (LOX) in synovial hyperplasia and pannus formation associated with rheumatoid arthritis (RA). Synovial, serum, and synovial fluid samples are collected from RA, osteoarthritis (OA), and knee injury patients and subsequently analyzed via HE staining, immunohistochemistry, and ELISA. Compared with those of the OA and injury groups, the RA synovium presents increased thickness, disorganized cell layers, increased microvascular density (MVD), and elevated LOX expression. Moreover, LOX levels are positively correlated with the MVD. Both synovial fluid and fibroblast-like synoviocytes (FLSs) derived from RA patients present significantly elevated concentrations of LOX. In vitro experiments reveal that LOX dose-dependently promotes the proliferation of FLSs derived from both RA patients and healthy individuals (MH7A/HFLS) by accelerating S/M-phase cell cycle progression while simultaneously stimulating angiogenesis in human umbilical vein endothelial cells (HUVECs). In contrast, the LOX inhibitor BAPN suppresses these effects. Mechanistic analysis further reveals that LOX increases the phosphorylation of the PI3K-AKT signaling pathway, an effect that is reversible by BAPN. In conclusion, LOX may induce abnormal fibroblast proliferation and endothelial neovascularization via activation of the PI3K/AKT pathway, thus aggravating synovial hyperplasia and pathological membrane formation in RA. These findings provide a theoretical foundation for the development of targeted LOX treatments for RA.