Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease involving joint and bone damage that is mediated in part by proteases and cytokines produced by synovial macrophages and fibroblast-like synoviocytes (FLS). Although current biological therapeutic strategies for RA have been effective in many cases, new classes of therapeutics are needed. We investigated anti-inflammatory properties of the natural alkaloid tryptanthrin (TRYP) and its synthetic derivative tryptanthrin-6-oxime (TRYP-Ox). Both TRYP and TRYP-Ox inhibited matrix metalloproteinase (MMP)-3 gene expression in interleukin (IL)-1β-stimulated primary human FLS, as well as IL-1β–induced secretion of MMP-1/3 by FLS and synovial SW982 cells and IL-6 by FLS, SW982 cells, human umbilical vein endothelial cells (HUVECs), and monocytic THP-1 cells, although TRYP-Ox was generally more effective and had no cytotoxicity in vitro. Evaluation of the therapeutic potential of TRYP and TRYP-Ox in vivo in murine arthritis models showed that both compounds significantly attenuated the development of collagen-induced arthritis (CIA) and collagen-antibody–induced arthritis (CAIA), with comparable efficacy. Collagen II (CII)-specific antibody levels were similarly reduced in TRYP- and TRYP-Ox-treated CIA mice. TRYP and TRYP-Ox also suppressed proinflammatory cytokine production by lymph node cells from CIA mice, with TRYP-Ox being more effective in inhibiting IL-17A, granulocyte-macrophage colony-stimulating factor (GM-CSF), and receptor activator of nuclear factor-κB ligand (RANKL). Thus, even though TRYP-Ox generally had a better in vitro profile, possibly due to its ability to inhibit c-Jun N-terminal kinase (JNK), both TRYP and TRYP-Ox were equally effective in inhibiting the clinical symptoms and damage associated with RA. Overall, TRYP and/or TRYP-Ox may represent potential new directions for the pursuit of novel treatments for RA.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease that involves inflammation and progressive damage to distal joints, as well as inflammation and injury to other organs of the body (Firestein, 2003; Sharif et al, 2018)
RA is a chronic destructive autoimmune disorder that commonly leads to significant joint destruction that is mediated in part by proteases and cytokines produced by macrophages and fibroblast-like synoviocytes (FLS)
We identify TRYP-Ox and possibly TRYP as potentially novel RA therapeutics that could be pursued in drug development
Summary
Rheumatoid arthritis (RA) is an autoimmune disease that involves inflammation and progressive damage to distal joints, as well as inflammation and injury to other organs of the body (Firestein, 2003; Sharif et al, 2018). Optimal therapeutic approaches should be developed to prevent inflammation, immune system dysregulation, and bone destruction associated with this disease, while still exhibiting enhanced safety and efficacy. Natural compounds have been considered as potential alternative or complementary treatments, as these compounds have been shown to possess a broader diversity in chemical space and, as a result, have significantly impacted drug development for many diseases (Hong, 2011). Many natural products have been shown to exhibit potential for treatment of inflammatory diseases (Lu et al, 2015) and have been evaluated in pre-clinical and clinical trials. Triptolide and its derivatives have been evaluated for their therapeutic effects in RA (Han et al, 2012; Tang and Zuo, 2012). The plant-derived drug paclitaxel has been shown to inhibit collagen-induced arthritis (CIA) in mice (Xu et al, 2019)
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