Table of Contents
An Overview of the NF-kB mechanism of pathophysiology in rheumatoid arthritis, investigation of the NF-kB ligand RANKL and related. nutritional interventions
Excerpt
NF-kB is identified as one of the main inflammatory pathways [[1], [2], [3]] in RA, the most studied pathophysiological mechanism for this Autoimmune Disease [4]. There is ongoing research on the potential impact of nutritional interventions influencing NF-kB as well as RA disease onset and outcomes, which highlights the utility of nutrients such as Omega 3 and Vitamin D [5]). This literature review with methodology based on the Cochrane Systematic Review Six [6] aims to explore the NF-kB and RANKL inflammatory mechanisms and also nutritional interventions which may ameliorate these.
In RA, NF-kB is identified as one of the main inflammatory pathways responsible for the expression of inflammatory response genes [2,4]. A number of pharmacological agents such as Corticosteroids have been identified as a potent treatment option [3,7,8], however, these have been recognized to have numerous side effects including an increased risk of developing osteoporosis, adrenal insufficiency and hyperlipidemia [9] in addition to unexplained Corticosteroid resistance phenomenon, found in up to 30% of RA cases [10]. NF-kB has a major role in homeostatic function of managing appropriate immune response and regulation of the cell cycle [11], which may be impaired by non-discriminative suppression [12]. Due to the potential suppression of immunological function, immunosuppression-related side effects and poor patient response to treatment, [13] highlights newer therapeutic options for RA such as osteoclast management by regulating RANKL levels responsible for increase, stimulation, maturation and proliferation of osteoclasts by using pharmaceutical agents such as Denosumab.
Over the last two decades research regarding dietary interventions and the impact on RA disease progression has been studied in human trials [14]. Despite these studies reporting positive outcomes, there is still a lack of overview of the mechanisms of action of foods and nutrients on specific RA related markers and pathways. Furthermore, whilst the majority of research including pharmacological and emerging nutritional interventions appears to be concentrating mainly on suppression of inflammation associated with the NF-kB pathway, more recent RA pathophysiological research is focusing on examining the importance of the NF-kB ligand RANKL and its role in bone degradation and osteoclast genesis. Tanaka (2018) calls for research investigating RANKL as a new therapeutic target in RA [16]. The expanding research into RANKL may be due to relatively new understanding that therapeutic strategy for RA needs to not only inhibit synovial inflammation but also to prevent bone erosion [17].This paper aims to examine the broader mechanisms of pathophysiology of NF-kB with a specific interest in the RANKL ligand relating to bone erosion. It further examines nutritional interventions, which exert positive effect on these mechanisms. Targeting mechanism of action of interventions to mechanisms of pathophysiology, which present as a priority for individuals supports personalized nutrition practice [18]. Findings from this review, therefore, further contribute to the understanding regarding the role of Vitamin D to support personalized nutrition practice in the management of RA.
Abstract
Nuclear Factor Kappa-Β (NF-kB) is recognized as one of the main inflammatory pathways in the Autoimmune Disease (AD) Rheumatoid Arthritis (RA), which exhibits high levels of inflammatory cytokines such as IL-1, TNFa and IL-6 linked to bone erosion and disease progression. NF-kB is also the most studied pathophysiological mechanism in RA, however, over the last few decades, a more recently discovered Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL), also linked to NF-kB activation and bone erosion, has been the topic of interest for research in the area of AD management. As the non-discriminative long term suppression of the NF-kB pathway by pharmacological agents in the management of RA has been linked with a number of side effects and with the discovery of the RANKL mechanism, which may present a more targeted approach to the management of the AD, there has been renewed interest in research on the potential impact of nutritional interventions influencing the NF-kB pathway, RANKL as well as RA disease outcomes.
Existing research highlights the potential utility of nutrients such as Omega 3 and Vitamin D, which may lower NF-kB activation in RA. There is, however, a gap in the knowledge of the effects of nutritional interventions on pathophysiological mechanisms contributing to RA and a more robust systematic analysis of whether nutrients or specific vitamins can have an effect on the NF-kB and RANKL main drivers of pathology in RA.
Findings from this study suggest the potential of Vitamin D supplementation in lowering the levels of RANKL and related markers/cytokines such as Th17 cell levels, OPG/RANKL ratio and CXCL10 pathway, which may present as a viable nutrition intervention for the management of RA.
The methodology of this review involved a Systematic Search of the Literature with a Critical Appraisal of papers. It incorporated three tranche searches of 1. review, 2. animal/in vitro and 3. intervention peer reviewed research published in the last 10 years, resulting in a total of 119 papers. Results provide an overview of the NF-kB pathway, a detailed mechanistic examination of the Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL) which is linked to bone erosion, and finally a review of nutritional interventions relating to this mechanism of pathophysiology. The accepted papers were critically appraised using SIGN50 for human studies and the ARRIVE guidelines for animal studies; the narrative was and the extracted information coded into key themes.