Wnt signaling drives stromal inflammation in inflammatory arthritis

The concept that fibroblasts are critical mediators of inflammation is an emerging paradigm. In rheumatoid arthritis (RA), they are the main producers of IL-6 as well as a host of other cytokines and chemokines. Their pathologic activation also directly causes cartilage and bone degradation. Yet, therapeutic agents specifically targeting fibroblasts are not available. Here, we find that Wnt receptors and modulators are predominantly expressed in stromal populations in the synovium. Importantly, non-canonical Wnt activation induces robust inflammatory gene expression including an abundance of cytokines and chemokines in synovial fibroblasts in vitro. Strikingly, the addition of Wnt ligands or inhibition of Wnt secretion exacerbates or reduces arthritis severity, respectively, in vivo in a murine model of inflammatory arthritis. These observations are relevant in human disease, as Wnt activation signatures are enhanced in fibroblasts derived from inflamed RA synovial tissue as well as fibroblasts across other inflammatory diseases. Together, these findings implicate Wnt signaling as a major driver of fibroblast-mediated inflammation and joint pathology. They further suggest that targeting the Wnt pathway is a therapeutically relevant approach to rheumatoid arthritis, particularly in patients who do not respond to conventional treatments and who often express fibroblast-predominant synovial phenotypes.