Macrophages regulated by cyclooxygenases promote tendon healing via Pla1a/Etv1 axis

Tendon injuries are often accompanied by limited self-healing and common complications, such as re-rupture and adhesion formation. In our previous studies, we discovered that inhibiting cyclooxygenases (COXs) through a sustainable nanoparticle/hydrogel released system prevented adhesion formation. Additionally, we observed a decrease in M1/M2 polarization in the microenvironment. To investigate the mechanism underlying M2 macrophage polarization, we developed a rat flexor tendon injury model and injected macrophages transfected with COX siRNAs. The results confirmed the positive effects of this treatment and identified important targets, namely phospholipase A1 member A (Pla1a) and ETS variant transcription factor 1 (Etv1). We conducted in vivo and in vitro studies based on Pla1a and Etv1. In the in vivo studies, Pla1a/nanoparticle/hydrogel treatment improved the ultimate strength of injured tendons and inhibited flexor tendon adhesion formation. In the in vitro studies, upregulation of Pla1a promoted tendon cell proliferation and suppressed cell apoptosis. Stimulation of Pla1a also downregulated the level of Etv1. Tendon cells transfected with Etv1 siRNAs demonstrated better cell viability and less cell apoptosis. Furthermore, adhesion formation was reduced by treatment with Etv1 siRNAs/nanoparticle/hydrogel. These findings suggest that COX siRNAs-regulated macrophages could enhance tendon healing via the Pla1a/Etv1 axis.