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

Abstract

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-α-mediated local inflammation. However, whether TNF-α in turn affects AS-MSC remains unknown. Herein, we further demonstrate that a high-concentration TNF-α treatment triggers enhanced directional migration of AS-MSC in vitro and in vivo, which enforces AS pathogenesis. Mechanistically, TNF-α leads to increased expression of ELMO1 in AS-MSC, which is mediated by a METTL14 dependent m6A 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.

Emerging Roles of Long Non-Coding RNAs in Ankylosing Spondylitis

“…AS is an autoimmune disease with poorly-defined etiology and pathogenesis ( 70 – 72 ). Thus, more effort is needed to elucidate the underlying pathobiology so as to develop novel, mechanism-driven therapeutics.…”

METTL14 benefits the mesenchymal stem cells in patients with steroid-associated osteonecrosis of the femoral head by regulating the m6A level of PTPN6

“…For instance, Liu et al discovered that METTL3 promoted BMSCs osteogenesis by mediating m6A methylation of BMP2 transcripts and supposed that METTL3 could mitigate ovariectomy-induced osteoporosis [ 29 ]. Xie et al revealed that TNF-α induced m6A modification in ELMO1 3′UTR triggers directional migration of mesenchymal stem cell in ankylosing spondylitis patients [ 30 ]. Wang et al elucidated a new pathogenesis of osteoporosis, that is, FTO mediates Runx2 mRNA demethylation to inhibit the osteogenic differentiation of BMSCs [ 31 ].…”

Expression and Clinical Significance of the m6A RNA-Binding Proteins YTHDF2 in Peripheral Blood Mononuclear Cells From New-Onset Ankylosing Spondylitis

“…The analyses indicated that the YTHDF2 and ALKBH5 mRNA expression in PBMC from patients with AS was significantly lower than in cells from the HC, whereas the mRNA expression of FTO , WTAP , METTL3 , and METTL14 was unchanged. Recently, Xie et al explored the level of ALKBH5, FTO, WTAP, METTL3, and METTL14 in MSC with or without tumor necrosis factor alpha (TNF-α) stimulation from patients with AS and showed inconsistent results that only METTL14 was clearly downregulated in MSC from AS ( 21 ). The causes for the conflicting consequences may be due to discrepancies in cell type and TNF-α stimulation.…”

“…Moreover, m6A modification and differential expression of key m6A regulators could use as diagnostic, prognostic, and therapeutic targets for many diseases ( 18 – 20 ). Moreover, Xie et al demonstrated that METTL14-dependent m6A modification of ELMO1 contributes to the directional migration of mesenchymal stem cell (MSC) in AS ( 21 ). Although the m6A modification can affect the function of MSC in AS, the feature of m6A modification in peripheral blood mononuclear cells (PBMCs) in human AS is still unclear.…”