Receptor activator of nuclear factor kappa-B ligand–TNF receptor associated factor 6–nuclear factor kappa-B–mitogen-activated protein kinase signaling axis (RANKL-TRAF6-NF-kappaB-MAPK axis)

The Receptor activator of nuclear factor kappa-B ligand (RANKL)–TNF receptor associated factor 6 (TRAF6)–nuclear factor kappa-B (NF-kappaB)–mitogen-activated protein kinase (MAPK) signaling axis is a central regulatory pathway in bone physiology and immune regulation [1, 7]. This axis is initiated by the binding of RANKL to its receptor RANK, which triggers the recruitment of the adapter protein TRAF6 to the receptor's cytoplasmic tail [2, 3]. TRAF6 acts as an E3 ubiquitin ligase, facilitating the activation of the I-kappa-B kinase (IKK) complex and various MAPKs, including JNK, p38, and ERK [5, 8]. These signaling events culminate in the activation of key transcription factors such as NF-kappaB and NFATc1, which are essential for the differentiation, fusion, and survival of osteoclasts [1, 9]. Dysregulation of this pathway, particularly its overactivation, is a primary driver of pathological bone resorption in diseases like osteoporosis, rheumatoid arthritis, and bone metastasis [6, 8]. Therapeutic strategies targeting this axis primarily involve the use of denosumab, a monoclonal antibody that neutralizes RANKL, thereby preventing the activation of the entire downstream cascade [1, 10]. Experimental approaches also explore the inhibition of TRAF6 or specific MAPK components to treat bone-destructive conditions [8].

Other names

RANKL/RANK/TRAF6 signaling pathwayRANKL-induced osteoclastogenic axisRANKL-RANK-TRAF6-NF-kappaB-MAPK pathwayRANKL-TRAF6-NF-kappaB-MAPKs signaling axis

The axis is modulated by inhibiting the binding of RANKL to its receptor RANK or by blocking the recruitment and activity of the adapter protein TRAF6, thereby suppressing the downstream activation of NF-kappaB and MAPK pathways required for osteoclastogenesis.