Notch and the regulation of osteoclast differentiation and function.

Notch 1 through 4 are transmembrane receptors that play a pivotal role in cell differentiation and function; this review addresses the role of Notch signaling in osteoclastogenesis and bone resorption. Notch receptors are activated following interactions with their ligands of the Jagged and Delta-like families. In the skeleton, Notch signaling controls osteoclast differentiation and bone-resorbing activity either directly acting on osteoclast precursors, or indirectly acting on cells of the osteoblast lineage and cells of the immune system. NOTCH1 inhibits osteoclastogenesis, whereas NOTCH2 enhances osteoclast differentiation and function by direct and indirect mechanisms. NOTCH3 induces the expression of RANKL in osteoblasts and osteocytes and as a result induces osteoclast differentiation. There is limited expression of NOTCH4 in skeletal cells. Selected congenital disorders and skeletal malignancies are associated with dysregulated Notch signaling and enhanced bone resorption. In conclusion, Notch signaling is a critical pathway that controls osteoblast and osteoclast differentiation and function and regulates skeletal homeostasis in health and disease.