Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation.

Osteoclasts are unique, multinucleated giant cells that decalcify and degrade the bone matrix. They originate from hematopoietic cells and their differentiation is dependent on a tumor necrosis factor (TNF) family cytokine, receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL), as well as macrophage-colony stimulating factor (M-CSF). Recent studies have unveiled the precise molecular mechanism underlying osteoclastogenesis. In particular, the discovery of nuclear factor of activated T cells c1 (NFATc1), the master regulator of osteoclastogenesis, has proven to be a breakthrough in this field. NFATc1 is activated by Ca2+ signaling induced by the activation of the immunoglobulin-like receptor signaling associated with immunoreceptor tyrosine-based activation motif (ITAM)-harboring adapters. The long-lasting Ca2+ oscillation, which is evident during osteoclastogenesis, may ensure the robust induction of NFATc1 through an autoamplification mechanism. Thus, intracellular Ca2+ is a critical attribute of osteoclastogenic signaling. In addition, osteoclasts are exposed to a very high extracellular Ca2+ concentration ([Ca2+]o) in the bone microenvironment and respond to the change in [Ca2+]o by increasing the intracellular Ca2+, which regulates diverse cellular functions. Investigation of the molecular mechanisms underlying the regulation of intracellular Ca2+ dynamics may open up new directions for therapeutic strategies in bone disease.