Molecular role of developmentally regulated GTP-binding protein 1 in coordinating osteoclast and osteoblast differentiation during bone remodeling

The developmentally regulated GTP-binding protein (DRG) family, comprising DRG1 and DRG2, plays pivotal roles in cellular differentiation. While DRG2 has been recognized as a key regulator of bone homeostasis, the biological significance of DRG1 in skeletal development has remained elusive. Here, we uncover a previously unappreciated and essential role for DRG1 in orchestrating the differentiation of both osteoclasts and osteoblasts through modulation of p38 MAPK signaling. Intriguingly, DRG1 downregulation enhances RANKL-induced p38 phosphorylation, thereby promoting osteoclastogenesis, while simultaneously facilitating BMP2-driven osteoblast differentiation via the same pathway. This dual regulatory capacity positions DRG1 as a molecular switch balancing bone resorption and formation. Notably, DRG1 and DRG2 exhibit opposing effects on osteoclast differentiation but converge in suppressing osteoblast maturation-yet their combined depletion does not yield additive effects, suggesting mechanistic independence. Despite its pronounced influence on cellular differentiation, DRG1 deficiency in vivo does not disrupt bone mass under physiological or pathological conditions, indicating a finely tuned equilibrium between its pro- and anti-osteogenic actions. These findings redefine DRG1 as a context-dependent modulator of skeletal remodeling and highlight its functional divergence from DRG2, offering new insights into the complexity of bone homeostasis regulation.