Receptor activator of nuclear factor kappa-B ligand–Receptor activator of nuclear factor kappa-B–Nuclear factor kappa-B–Nuclear factor of activated T-cells cytoplasmic 1 signaling axis (RANKL–RANK–NF-κB–NFATc1 axis)

The RANKL–RANK–NF-κB–NFATc1 signaling axis is a fundamental molecular pathway that regulates bone metabolism and immune function by controlling the development and activity of osteoclasts [1, 15]. The process is initiated when the Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL), a cytokine produced by osteoblasts and activated T cells, binds to its receptor RANK on the surface of osteoclast precursors [11, 14]. This interaction triggers a signaling cascade involving the recruitment of TRAF6, which activates the Nuclear Factor Kappa-B (NF-κB) pathway and subsequently induces the expression of the Nuclear Factor of Activated T-cells, Cytoplasmic 1 (NFATc1), the master transcription factor for osteoclastogenesis [3, 18]. Activation of this axis leads to the differentiation, fusion, and survival of bone-resorbing osteoclasts, making it a central player in physiological bone remodeling [12, 15]. Dysregulation of this pathway, often characterized by an overabundance of RANKL, is a primary driver of pathological bone loss in conditions such as osteoporosis, rheumatoid arthritis, and bone metastases from solid tumors [8, 9]. Therapeutic intervention, most notably with the monoclonal antibody denosumab, targets RANKL to inhibit its binding to RANK, thereby reducing osteoclast activity and preserving bone density in patients with high risk of skeletal-related events [2, 4].

Other names

RANKL/RANK/NF-κB/NFATc1 pathwayTNFSF11–TNFRSF11A–NFKB1–NFATC1 axisODF–RANK axisTRANCE–RANK axisRANKL–RANK–NFATc1 signaling pathway

Inhibition of RANKL binding to its receptor RANK, which prevents the recruitment of TRAF6 and subsequent activation of the NF-κB and NFATc1 signaling cascades, thereby blocking the differentiation, activation, and survival of bone-resorbing osteoclasts.