Mitogen-activated protein kinase (MAPK) signaling pathway leading to Nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and Proto-oncogene c-Fos (MAPK/c-Fos/NFATc1 axis)

The MAPK pathway leading to NFATc1 and c-Fos is a critical signaling axis primarily characterized in the context of osteoclastogenesis and bone resorption. This pathway is typically initiated by the binding of Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) to its receptor RANK, which triggers a cascade involving three major mitogen-activated protein kinase (MAPK) subfamilies: extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 (Lee et al., 2018, Molecules and Cells). These kinases collectively facilitate the induction and activation of the transcription factor c-Fos, a member of the AP-1 complex that is essential for the initial stages of osteoclast differentiation (Grigoriadis et al., 1994, Science). c-Fos, in turn, is indispensable for the robust induction of Nuclear Factor of Activated T-cells cytoplasmic 1 (NFATc1), which serves as the master regulator of osteoclast differentiation and function (Takayanagi et al., 2002, Nature). Dysregulation of this signaling axis is central to the pathogenesis of various metabolic bone diseases, including osteoporosis, rheumatoid arthritis, and bone metastases, where excessive osteoclast activity leads to pathological bone loss. While the pathway as a whole is a signaling sequence rather than a single molecular target, its individual components are highly druggable. Therapeutic strategies often involve inhibiting the upstream RANKL/RANK interaction (e.g., with Denosumab) or targeting specific MAPKs to suppress the downstream activation of NFATc1 and c-Fos. However, targeting this pathway requires careful management of safety concerns, as these signaling molecules also play essential roles in immune cell function and normal tissue homeostasis.

Other names

MAPK/c-Fos/NFATc1 signaling axisRANKL-induced MAPK pathwayOsteoclastogenic MAPK signaling cascade

Inhibition of the RANKL/RANK interaction or the phosphorylation of MAPK components (ERK, JNK, p38) to suppress the downstream transcriptional induction and activation of c-Fos and NFATc1.