Regulatory Mechanisms of Notch Signaling in Osteoclast Differentiation

Osteoclasts are primary bone-resorbing cells that play a critical role in bone remodeling. Two proteins crucial for osteoclast development are the receptor activator of NF-κB (RANK) and its ligand RANKL. Beside the RANKL/RANK system, other costimulatory signals, such as receptors with multiple immunoglobulin-like domains that are associated with tyrosine-based adapter motifs, are also involved in regulating osteoclast differentiation. We have recently found using genome-wide screening techniques that Notch family molecules are upregulated during RANKL-induced osteoclastogenesis, suggesting that Notch modulates signaling downstream of RANK. Although multiple lines of evidence indicate that Notch signaling dysfunction results in bone disease, the specific involvement for Notch in regulating osteoclastogenesis is still controversial. In this review, we introduce new findings about the role of Notch signaling in osteoclast differentiation, based on the results of other groups and our recent work.