Skeletal remodeling balance controlled by triad RANKL-RANK-osteoprotegerin discovered late 1990s as final common pathway for osteoclastogenesis. RANKL encoded by TNFSF11 gene chromosome 13q14 expressed as type II membrane protein and cleaved soluble form by metalloproteinases TACE from osteoblasts, osteocytes responding to parathyroid hormone, active vitamin D3, and inflammatory cytokines interleukin-1, tumor necrosis factor, and activated T cells expressing RANKL contributing to inflammatory bone loss. Binding to RANK receptor TNFRSF11A on monocyte-macrophage precursors belonging to tumor necrosis factor receptor family activates adaptor protein TRAF6 that recruits TAK1 activating NF-kB p50/p65, c-Fos, and calcium signaling via PLCγ leading to induction of master transcription factor NFATc1 autoamplification driving fusion into multinucleated 10-20 nuclei osteoclasts expressing tartrate-resistant acid phosphatase, cathepsin K cysteine protease degrading collagen type I telopeptides, and vacuolar proton pump ATPase acidifying resorption pit to pH 4.5 dissolving hydroxyapatite. Denosumab fully human IgG2-kappa antibody selected via transgenic XenoMouse displaying picomolar affinity for RANKL, mimicking endogenous decoy osteoprotegerin TNFRSF11B.
Ref:
Boyle et al Nature 2003 423:337 RANKL RANK OPG axis; Denosumab FDA label TNFSF11 neutralization osteoporosis.
