AP-1-dependent c-Fos activation by TREX1 drives M2 macrophage polarization and mitigates osteoarthritis progression

Inflammation significantly contributes to the pathogenesis of osteoarthritis (OA). Recent studies have elucidated the critical role of the three-prime repair exonuclease 1 (TREX1) in regulating inflammatory responses and oxidative stress. The aim of the study was to investigate the regulatory function of TREX1 in maintaining joint homeostasis subsequent to the destabilization of the medial meniscus (DMM) in a murine model.

Trex1-KO mice on a C57BL/6J background were utilized to investigate the role of Trex1 in OA. The DMM-induced OA model demonstrated histological and molecular alterations post-surgery, with immunofluorescence and Western blot analyses employed to assess chondrocyte characteristics and protein expression, respectively. In vitro experiments have been conducted where we established a co-culture system of macrophages and chondrocytes to investigate the regulatory role of Trex1 in macrophage polarization and its subsequent biological effects on chondrocytes, as well as the underlying mechanisms of these regulatory actions.

TREX1 deficiency intensifies OA progression in DMM mice, marked by increased oxidative stress, inflammation, and cartilage damage. TREX1 pretreatment in macrophages mitigates LPS-induced chondrocyte apoptosis and oxidative stress, an effect attenuated by si-c-Fos. AP-1 inhibition counters TREX1's protective impact on chondrocytes. TREX1 modulates macrophage polarization, influencing chondrocyte differentiation and matrix homeostasis in OA pathogenesis.

Overall, TREX1's influence on macrophage polarization affects chondrocyte function and cartilage homeostasis, making it a potential therapeutic target for OA treatment.