(5R)-5-hydroxytriptolide (LLDT-8) prevents collagen-induced arthritis through OPG/RANK/RANKL signaling in a rat model of rheumatoid arthritis

Abstract

Abstract. (5R)-5-hydroxytriptolide (LLDT-8) extracts fromTripterygium have anti-inflammatory, antineoplastic and immunity adjustment functions. The present study used a collagen-induced arthritis (CIA) model to evaluate whether LLDT-8 prevents collagen-induced arthritis, and investigated the signaling underlying this. Male Sprague-Dawley rats were induced to generate CIA, mimicking rheumatoid arthritis (RA). The presence of arthritis was determined using RA progression scores. The inflammatory cytokines interleukin (IL)-1β, IL-6 and nuclear factor-κB were detected using enzyme-linked immunosorbent assay kits. Induced nitric oxide synthase (iNOS) and matrix metalloprotease (MMP)-13 protein expression were measured using western blot analysis. Lastly, reverse transcription-quantitative polymerase chain reaction was used to evaluate osteoprotegerin (OPG) and receptor activator of nuclear factor κB (RANK) gene expression. LLDT-8 improved RA progression scores and reduced the incidence and severity of CIA. Furthermore, LLDT-8 administration inhibited collagen-induced inflammation and iNOS protein expression in arthritic rats. The current data indicated that MMP-13 production was suppressed and OPG/RANKL expression was increased by LLDT-8 treatment in the arthritic rat. The present results suggest that LLDT-8 attenuates CIA through OPG/RANK/RANK ligand signaling in a rat model of RA. IntroductionRheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that is characterized by erosive arthrosynovitis (1).The incidence of RA in females is more than that in males, at a ratio of 1:3 (2). The mortality rate of RA in worldwide populations varies from 0.01-0.05%, and prevalence rate is 0.18-1.07% (3). RA is also an impactful disease, resulting in labor loss and disability in China (2). According to US epidemiological investigation over the last 40 years, the difference in mortality rate between RA patients and the general population has increased (4). The risk of cognitive impairment for RA patients is higher than that of the general population (5). The etiology of RA is unclear. Previous studies suggest that RA is associated with genetic factors, infection, immunity and endocrine function (6,7).The main pathological characteristics of RA are hyperplasia of synovial cells and T cell accumulation during inflammation of synovial tissues, accompanied by pannus formation, followed by damage to the cartilage and bone (8). Finally, RA causes joint deformity and functional loss (9). These pathological changes may result from a combination of genetic mutations, activation of protooncogenes, lesions of synoviocytes, release of proinflammatory cytokines by inflammatory cells during infiltration of synovial tissues, chemotactic factors and enzymatic degradation of stromal proteins, amongst other factors (10). The etiology of RA is unclear, but it is universally believed to be a multifactorial disease, associated with genetic, environmental and infective factors (11). Autoimmunity may arise due to genetic factors, or as an ab...

Tougu Xiaotong capsule exerts a therapeutic effect on knee osteoarthritis by regulating subchondral bone remodeling

“…Previous studies proved that the regulation of bone metabolism occurs through the classical OPG/RANK/RANKL pathway, the direct and indirect functions of which are influenced by inflammatory factors, such as IL-1β, TNF-α, IL-6 and IL-17 (20,22,(43)(44)(45)(46)(47)(48). There are reports that TNF-α and IL-1β and other inflammatory factors can reduce OPG, stimulate RANKL and have a synergistic effect, resulting in increased bone resorption (47,49). In the present study, we found that the mRNA and protein expression of IL-1 and TNF-α in subchondral bone initially exhibited a significant increase in the model group and then decreased after treatment with TGXTC.…”

Therapeutic Effects of (5R)-5-Hydroxytriptolide on Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via lncRNA WAKMAR2/miR-4478/E2F1/p53 Axis

“…LLDT-8 has a variety of immunosuppressive activities and significant therapeutic effects in vitro and in vivo . The LLDT-8 prevents collagen-induced arthritis via inhibiting OPG/RANK/RANKL signaling in osteoclastogenesis and IFN-gamma signaling in T cells ( 12 , 13 ). However, it is still unknown whether LLDT-8 regulates FLS function during RA development.…”

“…Thus, LLDT-8 is suggested to be an optimal analog of triptolide ( 11 ). Studies have reported that LLDT-8 prevents collagen-induced arthritis (CIA) in animal models ( 12 , 13 ). LLDT-8 is now in phase II clinical trials, in China, for RA treatment ( 14 ).…”

Total Saponins from Nigella glandulifera Seeds Ameliorate Adjuvant-Induced Rheumatoid Arthritis in Rats by Inhibition of an Inflammatory Response and Bone Erosion

“…Given the crucial role that proinflammatory cytokines have in the induction and maintenance of RA, regulation of these cytokines on regulatory T cells (Tregs) can be a target to strengthen immune tolerance and protect against the formation of osteoclasts [ 12 ]. Synovitis is the principal cause of joint bone erosion, closely associated with lack of control of a number of regulators that maintain osteoclast homeostasis, such as increased receptor activator of nuclear factor 𝜅B ligand (RANKL) levels and decreased osteoprotegerin (OPG) [ 13 , 14 ]. Thus, the main purpose of current treatments for RA is to reduce the immuno-inflammatory response, inhibit the development of lesions and bone damage, and protect the function of joints.…”