Integrin-mediated inhibition of CCN1 attenuates angiogenesis and joint damage in experimental rheumatoid arthritis

Background: CCN1 is a matricellular protein with known proangiogenic and immunomodulatory properties. Its role in rheumatoid arthritis (RA) remains incompletely defined. We aimed to determine whether CCN1 acts as a biomarker of disease progression and a potential therapeutic target in RA. Methods: CCN1 expression was assessed in synovial tissues and endothelial cells (ECs) from RA patients and its regulation by TNF and IL-17 was evaluated. Serum CCN1 levels were measured in two independent RA cohorts, and their association with radiographic progression was analyzed using multivariable regression. The effects of CCN1 neutralization (monoclonal antibody), EC-specific CCN1 deletion (Cre:Lox in mBSA arthritis), CCN1 knockdown (shRNA in Tg197 mice), and pharmacologic integrin blockade (Cilengitide) were investigated in vitro and in vivo. Endpoints included endothelial proliferation, migration, angiogenesis, arthritis severity, joint damage, and T cell activation. Results: CCN1 was overexpressed in RA synovial tissues and ECs and was induced by TNF and IL-17. Elevated baseline serum CCN1 independently predicted radiographic progression, supporting its value as a circulating biomarker of structural damage. CCN1 neutralization reduced proliferation, migration, and tube formation in RA-derived ECs, while CCN1 invalidation markedly diminished their proangiogenic activity in vivo. Endothelial-specific CCN1 deletion and CCN1 knockdown in Tg197 mice both led to reduced clinical severity and joint destruction. Cilengitide abrogated CCN1-induced angiogenic responses in vitro and alleviated arthritis in Tg197 mice, reducing inflammation, structural damage, and effector T cell activation. Conclusions: CCN1 promotes RA pathogenesis by driving pathological angiogenesis and shaping the inflammatory microenvironment through αvβ3/β5 integrin signaling. Circulating CCN1 may serve as a predictive biomarker of joint damage, and targeting CCN1–integrin interactions represents a promising therapeutic approach in RA.