Human umbilical mesenchymal stem cell-derived exosomes alleviate bone destruction and regulate bone immunity via the aryl hydrocarbon receptor to treat rheumatoid arthritis

Objective

Rheumatoid arthritis (RA) can lead to joint deformity, loss of function, and even disability. Bone erosion is a common cause of disability in individuals with RA; bone resorption by osteoclasts (OCs) and bone immunity by regulatory T cells (Tregs) play key roles in this process. Human umbilical mesenchymal stem cells (HUMSCs) can be used to treat RA; however, the regulation of Tregs and OCs by HUMSCs and their therapeutic effects on RA have not been fully elucidated. This study aimed to reveal the effects of exosomes derived from HUMSCs carrying miRNA-150-5p on Tregs and OCs in individuals with RA and to provide innovative evidence for the ability of HUMSCs to alleviate RA.

Methods

First, we used collagen-induced arthritis (CIA) model mice to verify the efficacy of miR-150-5p^mimic-Exos and explored their effects on bone erosion in mouse joints and on Tregs in the lymph nodes. Subsequently, miR-150-5p^mimic-Exos and the aryl hydrocarbon receptor (AhR) inhibitor CH223191 were used in in vitro OCs, Tregs, and OC-Treg coculture systems to determine whether miR-150-5p^mimic-Exos regulate bone immune microenvironment homeostasis via AhR.

Results

Treatment with miR-150-5p^mimic-Exos effectively alleviated bone damage to the ankle and knee joints in CIA model mice, inhibited OC differentiation, activated the immunosuppressive function of Tregs, and regulated bone immunity by increasing the expression of AhR/CYP1A1 signalling pathway genes such as Ahr, Arnt, Ahrr, Cyp1a1/1a2 and Cyp1b1 in OCs and Tregs. By coculturing Tregs and OCs, the ability of the miR-150-5p^mimic-Exos to inhibit OC differentiation was further strengthened.

Conclusions

This study confirmed that miR-150-5p^mimic-Exos can reduce bone destruction in mice with CIA. We first showed that miR-150-5p^mimic-Exos acted on a Treg-OC coculture system to alleviate bone erosion and regulate bone immunity. This study is expected to provide new ideas for the treatment of RA.