CaMKIV negatively regulates osteoblast differentiation by modulating c-Fos and NFATc1 signaling: an in vitro and in vivo mechanistic study.

The CaMKIV-c-Fos-NFATc1 axis is established in osteoclastogenesis, but its role in osteoblasts is largely unexplored. We show that this axis suppresses osteoblast differentiation and bone formation. Silencing CaMKIV increased osteogenic gene expression and mineralization, whereas overexpressing c-Fos or NFATc1 reduced osteoblast activity. Mechanistically, CaMKIV binds c-Fos and inhibits its ubiquitination, stabilizing c-Fos and elevating NFATc1. NFATc1, in turn, impairs Runx2 acetylation by competing for PCAF, thereby attenuating osteoblast maturation. Pharmacological CaMKIV inhibition with STO-609 increased bone formation in vitro and enhanced ectopic bone formation in vivo, supporting CaMKIV as a potential anabolic target for bone regeneration. [BMB Reports 2026; 59(4): 235-241].