Receptor activator of nuclear factor kappa-B ligand–Nuclear factor kappa-B signaling axis (RANKL–NF-κB axis) (RANKL–NF-κB axis)

The Receptor activator of nuclear factor kappa-B ligand (RANKL)–Nuclear factor kappa-B (NF-κB) signaling axis is a central regulatory pathway in bone metabolism and immune function [1]. RANKL, a cytokine of the TNF superfamily, is produced by osteoblasts and activated T cells and binds to its receptor, RANK, on the surface of osteoclast precursors [2]. This interaction triggers a signaling cascade that activates the NF-κB transcription factor, which is essential for the differentiation, maturation, and survival of osteoclasts [3]. Overactivation of this axis leads to excessive bone resorption, contributing to the pathogenesis of osteoporosis, rheumatoid arthritis, and bone destruction in metastatic cancer [4]. Therapeutic targeting of this axis is primarily achieved through denosumab, a monoclonal antibody that binds RANKL and prevents its interaction with RANK, effectively mimicking the natural decoy receptor osteoprotegerin (OPG) [5]. While highly effective in increasing bone density and reducing fracture risk, modulation of this axis requires careful monitoring for side effects such as hypocalcemia and osteonecrosis of the jaw [6].

Other names

RANKL/RANK/NF-κB pathwayRANKL-RANK signaling axisTNFSF11-TNFRSF11A-NF-κB axisRANKL-RANK-OPG system

The primary mechanism involves the inhibition of RANKL binding to the RANK receptor, which prevents the recruitment of TRAF6 and the subsequent activation of the NF-κB transcription factor, thereby halting osteoclast differentiation and activity.