TNF-α-mediated m6A modification of ELMO1 triggers directional migration of mesenchymal stem cell in ankylosing spondylitis

Ankylosing spondylitis (AS) is a type of rheumatic disease characterized by chronic inflammation and pathological osteogenesis in the entheses. Previously, we demonstrated that enhanced osteogenic differentiation of MSC from AS patients (AS-MSC) resulted in pathological osteogenesis, and that during the enhanced osteogenic differentiation course, AS-MSC induced TNF-alpha-mediated local inflammation. However, whether TNF-alpha in turn affects AS-MSC remains unknown. Herein, we further demonstrate that a high-concentration TNF-alpha treatment triggers enhanced directional migration of AS-MSC in vitro and in vivo, which enforces AS pathogenesis. Mechanistically, TNF-alpha leads to increased expression of ELMO1 in AS-MSC, which is mediated by a METTL14 dependent m(6)A modification in ELMO1 3 ' UTR. Higher ELMO1 expression of AS-MSC is found in vivo in AS patients, and inhibiting ELMO1 in SKG mice produces therapeutic effects in this spondyloarthritis model. This study may provide insight into not only the pathogenesis but also clinical therapy for AS. Abnormal functions of mesenchymal stem cells (MSC) contribute into the pathogenensis of ankylosing spondylitis (AS). Here, the authors show that TNF-alpha at high concentration induces enhances migration of AS-MSC through METTL14 mediated m6A modification of the ELMO1 3 ' UTR.

Automated summary

Abnormal functions of mesenchymal stem cells (MSC) contribute to the pathogenesis of ankylosing spondylitis (AS). The authors demonstrate that high concentration of TNF-alpha induces enhanced migration of AS-MSC through METTL14 mediated m6A modification of the ELMO1 3 ' UTR.