Rheumatoid arthritis severity is mediated by crosstalk between synoviocytes and mature osteoclasts through a calcium and cytokine feedback loop

Fibroblast-like synoviocytes (FLSs) and osteoclasts are central cells in the maintenance of joint homeostasis. Rheumatoid arthritis (RA) is a chronic inflammatory disease of joints that induces cytokine-activated FLSs and progressive bone erosion. Interactions between FLSs and other cells, such as T cells and B cells, have been recognized in the development of RA. Here we hypothesized that calcium released from bone by mature osteoclasts might activate FLSs, which are also affected by inflammatory cytokines in the inflamed synovium. Osteoclastogenesis occurs in the presence of cytokine-stimulated FLS medium, and calcium released from the bone disc activates FLS migration. We first investigated the calcium and cytokine feedback loop between FLSs and osteoclast maturation. Moreover, by addressing the role of the sodium-bicarbonate cotransporter NBCn1 in osteoclastogenesis, we found that the inhibition of NBCn1 attenuated the infinite calcium and cytokine feedback loop between FLSs and osteoclasts. In a collagen-induced arthritis mouse model, the inhibition of NBC reduced the RA pathological phenotype and bone resorption area in the femur. These results suggest that modulation of the crosstalk between FLSs and osteoclasts by inhibiting the calcium and cytokine feedback loop could be considered to develop pioneering strategies to combat RA severity and dysregulated bone homeostasis. Rheumatoid arthritis is a painful condition that damages joints and bones. Despite treatment advances, some patients do not respond well to current therapies. Researchers explored a new approach to address this issue. They focused on calcium and cytokines in RA. The study involved 16 patients and used mouse models to understand how these elements affect joint damage. The researchers found that Ca2+ from bones and inflammatory cytokines increase the activity of fibroblast-like synoviocytes, cells that contribute to joint damage. They discovered that inhibiting a protein called NBCn1, which helps cells move, could reduce this harmful activity. They used a drug called S0859 to block NBCn1 in RA-induced mice, which decreased bone damage and inflammation. The study suggests that targeting NBCn1 could be a new way to treat RA, especially for those who do not respond to existing treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.