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

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.

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.

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.

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.