Abstract

BackgroundThe aim of this study was to investigate the regulative activity of (5R)-5-hydroxytriptolide (LLDT-8) on receptor activator of nuclear factor κ-B ligand (RANKL)/receptor activator of nuclear factor κ-B (RANK)/Osteoprotegerin (OPG) system in rheumatoid arthritis (RA) and its anti-osteoclastogenesis mechanism.MethodsThe expression of OPG, RANK and RANKL in CD3+ T leukomonocytes in both peripheral blood and synovial fluid of RA patients was evaluated by flow cytometry. The levels of interleukin (IL) 1β, IL-6, IL-10, IL-21 and IL-23 in the supernatants of peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were assayed by ELISA. Tartaric acid phosphatase (TRAP) staining was used to identify the osteoclast-like cells derived from RAW264.7. Western blotting analysis was used to check the downstream molecules of RANKL.ResultsLLDT-8 increased the rate of OPG expression in CD3+ T leukomonocytes in peripheral blood as well as the ratio of OPG/RANKL in both peripheral blood and synovial fluid. LLDT-8 inhibited IL-1β, IL-6, IL-21 and IL-23 secretion, but promoted the secretion of IL-10 in the supernatants of PBMCs and SFMCs. In addition, LLDT-8 decreased the number of TRAP-positive cells derived from RAW264.7 in the presence of RANKL and M-CSF. Furthermore, LLDT-8 also inhibited the expression of p-IκB, a key regulator of RANKL signaling pathway.ConclusionsLLDT-8 exerts its anti-osteoclastogenesis effect in RA probably through regulating RANKL/RANK/OPG system and its downstream signaling pathway as well as cytokine productions.

Highlights

  • The aim of this study was to investigate the regulative activity of (5R)-5-hydroxytriptolide (LLDT-8) on receptor activator of nuclear factor κ-B ligand (RANKL)/receptor activator of nuclear factor κ-B (RANK)/Osteoprotegerin (OPG) system in rheumatoid arthritis (RA) and its anti-osteoclastogenesis mechanism

  • Our work suggested that LLDT-8 upregulated OPG expression in CD3+T leukomonocytes in peripheral blood as well as the ratio of OPG/Receptor activator of nuclear factor κ-B ligand (RANKL) in both peripheral blood and synovial fluid, and it inhibited inflammatory cytokine secretion in the supernatants of peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs)

  • The results showed that LLDT-8 up-regulated OPG expression on CD3+ T leukomonocyte in peripheral blood at doses of 25 nM and 50 nM (Figure 1B), and increased the ratio of OPG/RANKL at the dose of 50 nM (Figure 1C)

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Summary

Introduction

The aim of this study was to investigate the regulative activity of (5R)-5-hydroxytriptolide (LLDT-8) on receptor activator of nuclear factor κ-B ligand (RANKL)/receptor activator of nuclear factor κ-B (RANK)/Osteoprotegerin (OPG) system in rheumatoid arthritis (RA) and its anti-osteoclastogenesis mechanism. Methods: The expression of OPG, RANK and RANKL in CD3+ T leukomonocytes in both peripheral blood and synovial fluid of RA patients was evaluated by flow cytometry. Tripterygium Wil’fordii Hook.F, belonging to plants of the genus Euonymus Corey Gong, is a traditional Chinese medicine, the extracts of which have a variety of pharmacological effects, such as anti-inflammatory, antibiosis, antifertility, immunosuppression, anti tumor and etc. They are widely used in the treatment of rheumatic disease, autoimmune disease, organ transplantation, nephroma, asthma and tumor [2].

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