Mechanistic insights into NETs-induced osteogenesis inhibition in BMSCs of rheumatoid arthritis

In the field of chronic inflammatory rheumatism, while neutrophil extracellular traps (NETs) have been recognized as contributors to the pathogenesis of rheumatoid arthritis (RA), the underlying mechanism of the abnormal interaction between NETs and bone marrow mesenchymal stem cells (BMSCs) has remained unclear. Our study made several key findings. Firstly, we discovered that the osteogenic differentiation ability of BMSCs in RA patients was reduced. Additionally, we found that the increased production of NETs in RA patients impaired bone formation by weakening the osteogenic capacity of BMSCs. Specifically, NETs activated the NF-κB pathway in BMSCs, suppressing the expression of bone morphogenetic protein 2 (BMP2) and thus inhibiting osteogenesis, which could be counteracted by an NF - κB inhibitor. Moreover, NETs promoted BMSCs to secrete interleukin-8 (IL-8), attracting more neutrophils into the bone marrow. These findings highlight the role of NETs-induced activation of the p65/NF-κB pathway in inhibiting BMSC osteogenesis in RA and suggest that targeting p65 may be a potential therapeutic strategy for RA.