PSTPIP2 regulates synovial macrophages polarization and dynamics via ERβ in the joint microenvironment

The cytoskeletal protein, PSTPIP2, is associated with inflammation and is predominantly expressed in macrophages. Previous data have shown that PSTPIP2 inhibits articular bone damage in arthritic rats. The aim of this study is to explore the molecular mechanism of PSTPIP2's resistance to bone erosion.

In the current study, peripheral blood and surgically excised synovial tissue from RA patients, DBA/1 mice, Pstpip2^CreR26-ZsGreen reporter mice, and Esr2^fl/fl/Adgre-Cre tool mice were used for in vivo studies. Adeno-associated viral vector was used to overexpress PSPTIP2 protein in vivo.

We found that The level of PSTPIP2 in synovial macrophages is negatively correlated with RA disease activity, which is mediated by synovial macrophages polarization. PSTPIP2^hi synovial macrophages form a tight immunological barrier in the lining layer. Notably, the ability of PSTPIP2 to regulate synovial macrophages polarization is dependent on ERβ. Additionally, PSTPIP2 regulates the dynamics of synovial macrophages via ERβ.

Together, this study reveals that PSTPIP2 regulates synovial macrophages polarization and dynamics via ERβ to form an immunological barrier (F4/80⁺PSTPIP2^hi cell-enriched zone) for the joints. Thus, local modulation of PSTPIP2 expression in the joint microenvironment may be a potential strategy for controlling bone erosion in rheumatoid arthritis. PSTPIP2 regulates synovial macrophages polarization and dynamics via ERβ to form F4/80⁺PSTPIP2^hi cellular barrier in joint microenvironment.