Notch in skeletal physiology and disease

Abstract

Notch (Notch1 through 4) are transmembrane receptors that play a fundamental role in cell differentiation and function. Notch receptors are activated following interactions with their ligands in neighboring cells. There are five classic ligands termed Jagged (Jag)1 and Jag2 and Delta-like (Dll)1, Dll3, and Dll4. Recent work has established Notch as a signaling pathway that plays a critical role in the differentiation and function of cells of the osteoblast and osteoclast lineages and in skeletal development and bone remodeling. The effects of Notch are cell-context dependent, and the four Notch receptors carry out specific functions in the skeleton. Gain- and loss-of-function mutations of components of the Notch signaling pathway result in a variety of congenital disorders with significant craniofacial and skeletal manifestations. The Notch ligand Jag1 is a determinant of bone mineral density, and Notch plays a role in the early phases of fracture healing. Alterations in Notch signaling are associated with osteosarcoma and with the metastatic potential of carcinoma of the breast and of the prostate. Controlling Notch signaling could prove useful in diseases of Notch gain-of-function and in selected skeletal disorders. However, clinical data on agents that modify Notch signaling are not available. In conclusion, Notch signaling is a novel pathway that regulates skeletal homeostasis in health and disease.

The down‐regulation of Notch 1 signaling contributes to the severity of bone loss in aggressive periodontitis

“…Notch 2 was previously found to play a major role in suppression of osteoblastogenesis and promotion of osteoclastogenesis . This effect was mostly exerted by induction of RANK in cells of the osteoblast lineage and consequent RANKL‐induced osteoclastogenesis . Based upon our results a putative mechanism of bone loss in periodontitis is proposed in Figure .…”

“…The bone destruction seen in periodontitis arises as a consequence of an aberrant activation of host immune system and its progression and severity are mainly attributed to complex interactions between bone‐remodeling cells and immunoregulatory mediators . Notch signaling pathway acts as an important regulator of bone‐remodeling processes, both in physiological and pathological conditions, controlling differentiation and functions of the osteoblastic and osteoclastic lineages . This pathway has also a prominent role in the differentiation and function of immunomodulatory cells in innate and adaptive immune response .…”

Interactions between Muscle and Bone—Where Physics Meets Biology

“…Besides its role in muscle physiology (see Section 3.2.2), Notch signaling has also been reported to be involved in skeletal physiology. We and others recently reported that this pathway is mechanosensitive in skeletal precursors [58,114]. Similarly, the Hippo pathway has gained attention as an important pathway in mechanotransduction and skeletal physiology.…”

Notch Signaling in Skeletal Development, Homeostasis and Pathogenesis

“…Notch activation in committed osteoblasts leads to osteosclerosis by increased immature osteoblasts due to inhibition of terminal differentiation of osteoblast. When Notch signaling is activated in osteocytes, it shows high bone mass due to reducing bone resorption ( Figure 2) [70,[73][74][75][76][77]. Recent studies have shown several interesting mechanistic aspects of Notch function in modulating osteoblast differentiation.…”