Transforming growth factor-β enables NFATc1 expression during osteoclastogenesis

Osteoclastogenesis is dependent on distinct stimuli that prime and activate osteoclast differentiation. One cytokine needed to prime monocytes for osteoclastogenesis is TGF-β, which enables and augments RANKL and TNF-α-induced osteoclast differentiation. However, the precise time-period during which this occurs and the molecular mechanism mediating this action are unknown. We report here TGF-β prime monocytes for osteoclast formation within 24 h by regulating expression of NFATc1, a key osteoclastic transcription factor. TGF-β directly induces cytoplasmic NFATc1 expression within 24 h, but is unable to stimulate NFATc1 nuclear translocation. Furthermore, RANKL-induced NFATc1 expression is dependent on the presence of TGF-β during the early stages of osteoclastogenesis. Similarly, TNF-α activates osteoclastogenesis by stimulating translocation of TGF-β-induced NFATc1. In light of these findings, it is apparent that osteoclast formation is dependent on coordinated interactions between TGF-β and RANKL/TNF-α that regulate the expression and intracellular distribution of NFATc1 during early stages of osteoclast differentiation.