Notch Signaling and the Skeleton

Notch 1 to 4 receptors are important determinants of cell fate and function, and Notch signaling plays an important role in skeletal development and bone remodeling. After direct interactions with ligands of the Jagged and Delta-like families, a series of cleavages release the Notch intracellular domain (NICD), which translocates to the nucleus where it induces transcription of Notch target genes. Classic gene targets of Notch are hairy and enhancer of split (Hes) and Hes-related with YRPW motif (Hey). In cells of the osteoblastic lineage, Notch activation inhibits cell differentiation and causes cancellous bone osteopenia because of impaired bone formation. In osteocytes, Notch1 has distinct effects that result in an inhibition of bone resorption secondary to an induction of osteoprotegerin and suppression of sclerostin with a consequent enhancement of Wnt signaling. Notch1 inhibits, whereas Notch2 enhances, osteoclastogenesis and bone resorption. Congenital disorders of loss-and gain-of-Notch function present with severe clinical manifestations, often affecting the skeleton. Enhanced Notch signaling is associated with osteosarcoma, and Notch can influence the invasive potential of carcinoma of the breast and prostate. Notch signaling can be controlled by the use of inhibitors of Notch activation, small peptides that interfere with the formation of a transcriptional complex, or antibodies to the extracellular domain of specific Notch receptors or to Notch ligands. In conclusion, Notch plays a critical role in skeletal development and homeostasis, and serious skeletal disorders can be attributed to alterations in Notch signaling. (Endocrine Reviews 37: 223-253, 2016) I. Introduction A. Notch receptors B. Skeletal development and bone remodeling II. Notch Signaling A. Notch ligands B. Notch receptors C. Notch intracellular signaling D. Notch target genes III. Genetic Tools to Study Notch Signaling in the Skeleton A. Notch misexpression B. Conditional Notch misexpression and Cre driver lines IV. Notch Signaling, Skeletal Development, and Homeostasis A. Role of Notch in chondrogenesis and skeletal development B. Notch regulation of osteoblast differentiation and function C. Notch regulation of osteocyte function D. Notch regulation of osteoclastogenesis and bone resorption V. Role of Hes and Hey in Skeletal Homeostasis VI. Notch and Skeletal Diseases A. Skeletal congenital diseases associated with lossof-Notch function B. Skeletal congenital diseases associated with gainof-Notch function C. Role of Notch in primary and metastatic bone tumors D. Fracture repair and Notch signaling E. Notch and osteoarthritis VII. Controlling Notch Signaling A. Biochemical inhibitors of Notch signaling B. Inhibitors of the Notch transcription complex formation C. Antibodies to Notch and Notch ligands VIII. Conclusions