Rapgef3 modulates macrophage reprogramming and exacerbates synovitis and osteoarthritis under excessive mechanical loading.

Evidence indicates that mechanical loading plays an important role in osteoarthritis (OA) progression, while the specific pathological changes of the synovium under excessive mechanical loading are unclear. Results showed that excessive mechanical loading caused pro-inflammation of synovial macrophages, which has been confirmed to exist in OA. High Rapgef3 expression level was found in RNA sequencing of RAW246.7 subjected to 0.5 Hz and 20% cyclic tensile strain. We verified this in the synovium of patients with OA and destabilization of the medial meniscus (DMM)-OA mice. Interestingly, the Rapgef3 content of chondrocytes was very low. Primary chondrocytes treated with Rapgef3 alone did not show metabolic phenotype, but an OA phenotype appeared when treated with Rapgef3-stimulated macrophage culture supernatant. Mechanically, excessive mechanical loading activated p65-nuclear factor κB (NF-κB) pathway through Rapgef3, which promoted the inflammation of macrophage, resulting in severe articular cartilage injury. Intra-articular Rapgef3 knockout reversed synovitis and cartilage degeneration, which might provide a therapeutic target for OA.