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2016 ; 37
(3
): 223-53
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Notch Signaling and the Skeleton
#MMPMID27074349
Zanotti S
; Canalis E
Endocr Rev
2016[Jun]; 37
(3
): 223-53
PMID27074349
show ga
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.
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