Mesothelin as a biomarker and potential therapeutic target in rheumatoid arthritis bone destruction.

Mesothelin (MSLN) is implicated in multiple biological processes, notably in modulating immune responses. However, the role of MSLN in osteoclastogenesis remains underexplored. Here we reveal that the level of MSLN was significantly elevated in rheumatoid arthritis (RA) patients, as well as in collagen-induced arthritis (CIA) animals. Pharmacological and genetic inhibition of MSLN significantly impair osteoclast differentiation and bone resorption. In the animal model, down-regulation of MSLN effectively alleviates bone destruction. Further investigation unravels that MSLN directly interacts with phosphatidylinositol 3-kinase (PI3K), resulting in the activation of the PI3K/protein kinase B (AKT) signaling pathway, which subsequently induces the expression and translocation of nuclear factor of activated T cells 1 (NFATc1), thereby promoting osteoclast differentiation. Overall, our findings indicate that MSLN could serve as a valuable prognostic marker for bone destruction in RA, and targeting MSLN may offer a therapeutic strategy for RA-related bone destruction.