RANK/RANKL/OPG Signaling in the Brain: A Systematic Review of the Literature

Abstract

Together with its dominant immunological and bone remodeling involvement, RRO axis, comprising of receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) signaling, is as well-implicated in CNS functioning and corresponding pathologies. The CNS aspects of RANKL/RANK/OPG (RRO) axis were systematically reviewed. With search 10 databases, and 7 additional resources from first article publication to July 2019, resulted in total 2,222 hits, from which 33 relevant articles were selected. The elements of RRO axis in CNS include cells involved in neuroinflammation, predominantly in microglia, but as well in resident macrophages and inflammatory cells migrating across the blood-brain barrier. The expression in neurons and oligodendrocytes is mainly confined to processes of differentiation and cell death. RRO axis tunes the neuroinflammatory response, depending on the molecular, cellular and pathological context. RANK/RANKL signaling is neuroprotective in TLR-mediated inflammation, while OPG seems detrimental in stroke, but beneficial in multiple sclerosis. The levels of RRO axis elements can serve as biomarkers in the blood and cerebrospinal fluid. They act as neuroprotectant after brain damage even being implicated in body weight-and thermo-regulation. As derivatives of RRO axis already exist as therapeutic agents in bone remodeling, it would be intriquing to see if these or new RRO-based pharmaceuticals would appear effective in CNS therapies.

Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and signs of neurodegeneration: a prospective cross-sectional study

“…Exploiting microglia, neuronal markers and neuroimaging, we investigated consequences of COVID-19-induced BBB impairment on cerebral integrity. TNFRSF11B, a decoy receptor for RANKL, was the sole CSF discriminant between class III and ICs, leading to microglia overstimulation (36). Importantly, we detected concurring elevated RANKL CSF/plasma ratios in class III, which underscores the relevance of increased TNFRSF11B levels.…”

Jianpi Qingchang Bushen decoction improves inflammatory response and metabolic bone disorder in inflammatory bowel disease-induced bone loss

“…Several pro-inflammatory cytokines, including IL-1β, TNF-α, IL-6, and IL-8 increase in IBD and have been shown to stimulate osteoclast differentiation[ 48 ]. Studies have suggested that the abnormal intestinal tract immune response in IBD leads to injury and inflammation of the intestinal mucosa, activation of the RANK /RANKL/OPG signaling pathway, changes in the bone conversion rate, osteoclast activation, and bone loss, leading to IBD-induced osteoporosis[ 21 , 49 , 50 ]. These results highlight the interactions between inflammation and the RANK/RANKL/OPG signaling pathway during the development of osteoporosis in IBD.…”

Protective Effect of TNFRSF11A rs7239667 G > C Gene Polymorphism on Coronary Outcome of Kawasaki Disease in Southern Chinese Population

“…TNFR family is composed of TNFRSF8, OPG, DCR3, etc., and is a growing superfamily with extracellular homologous sequences (Darnay and Aggarwal, 1999;Inoue et al, 2000;Aggarwal, 2003). As an activator of NF-κB receptor, TNFRSF11A is also a member of the tumor necrosis factor receptor superfamily (Yang et al, 2019;Glasnovic et al, 2020). Yang et al (2019) indicated that RANKL (a specific ligand of TNFRSF11A) rs2277438 polymorphism increased the risk of rheumatoid disease.…”