Triptolide attenuates inhibition of ankylosing spondylitis-derived mesenchymal stem cells on the osteoclastogenesis through modulating exosomal transfer of circ-0110634

Abstract

Background: Ankylosing spondylitis (AS) is featured by chronic inflammation of the sacroiliac joints and spine as well as pathological new bone formation. Osteoclastogenesis is a critical part in the development of bone formation. Circular RNAs (circRNAs) are recent research hotspot in the RNA field while rarely reported in osteoclastogenesis. Methods: AS mesenchymal stem cells (ASMSCs) and healthy donor mesenchymal stem cells (HDMSCs) were co-cultured with peripheral blood mononuclear cells (PBMCs). RT-qPCR was applied to detect the expression level of circ-0110634 in different exosomes. TRAP staining and TRAP activity detection were performed to identify the effect of circ-0110634 overexpression on osteoclastogenesis. Bioinformatics analysis and mechanism investigation were conducted to explore the downstream molecular mechanism of circ-0110634. Results: The effect of ASMSCs on PBMCs osteoclastogenesis is weaker than that of HDMSCs. Circ-0110634 had higher expression in ASMSCs exosomes than HDMSCs exosomes. Circ-0110634 overexpression suppressed the osteoclastogenesis. Circ-0110634 bound to both TNF receptor associated factor 2 (TRAF2) and tumor necrosis factor receptor II (TNFRII). Circ-0110634 also accelerated the dimerization of TRAF2 to induce TRAF2 ubiquitination and degradation. Circ-0110634 repressed the interplay between TRAF2 and TNFRII to inactivate the nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK) pathways. Triptolide promoted the osteoclastogenesis of ASMSCs exosomes-treated PBMCs via decreasing the exosomal transference of circ-0110634 in a dose-dependent manner. Consistently, triptolide treatment stimulated osteoclastogenesis to alleviate the arthritis of DBA/1 mice through suppressing circ-0110634. Conclusion: Our study confirmed that triptolide targets circ-0110634 to ease the burden of AS patients. The Translational potential of this article: This study suggests triptolide targets circ-0110634 to regulate osteoclastogenesis, which provides a novel potential target in triptolide treatment for AS patients.

Keywords

• Circ-0110634
• Triptolide
• Osteoclastogenesis
• Ubiquitination
• TRAF2