Receptor activator of nuclear factor kappa-B ligand (RANKL)–Receptor activator of nuclear factor kappa-B (RANK) signaling pathway (RANKL–RANK signaling)

The Receptor activator of nuclear factor kappa-B ligand (RANKL)–Receptor activator of nuclear factor kappa-B (RANK) signaling pathway is a fundamental molecular axis regulating bone metabolism and immune homeostasis [1, 3]. This cascade is initiated when RANKL, a member of the tumor necrosis factor (TNF) superfamily, binds to its cognate receptor RANK on the surface of osteoclast precursors and mature osteoclasts [4, 9]. This interaction recruits adaptor proteins like TRAF6, triggering downstream signaling through NF-kB, MAPK, and NFATc1 pathways, which are essential for the differentiation, activation, and survival of bone-resorbing cells [3, 14]. The pathway is naturally regulated by osteoprotegerin (OPG), a decoy receptor that neutralizes RANKL to prevent excessive bone loss [3, 15]. Dysregulation of the RANKL–RANK axis, typically manifested as an elevated RANKL/OPG ratio, is a primary driver of pathological bone resorption in diseases such as postmenopausal osteoporosis, rheumatoid arthritis, and bone metastases [1, 2, 11]. In oncology, the pathway not only facilitates the "vicious cycle" of bone destruction but also promotes tumor cell migration and immune evasion [7, 11]. The clinical significance of this pathway is underscored by the success of denosumab, a monoclonal antibody that targets RANKL to treat bone-related conditions [2, 10]. Beyond its skeletal roles, the pathway is involved in lymph node organogenesis and mammary gland development, highlighting its multifaceted biological impact [3, 4].

Other names

TNFSF11–TNFRSF11A signalingRANKL/RANK/OPG axisTRANCE/RANK signalingOsteoclast differentiation factor (ODF) signaling

Inhibition of RANKL binding to the RANK receptor, thereby preventing the activation of downstream signaling pathways (e.g., NF-kB, NFATc1) required for osteoclast differentiation, activation, and survival.