Abstract
Notch1-4 receptors and their signaling pathways are expressed in almost all organ systems and play a pivotal role in cell fate decision by coordinating cell proliferation, differentiation and apoptosis. Differential expression and activation of Notch signaling pathways has been observed in a variety of organs and tissues under physiological and pathological conditions. Bone tissue represents a dynamic system, which is constantly remodeled throughout life. In bone, Notch receptors have been shown to control remodeling and regeneration. Numerous functions have been assigned to Notch receptors and ligands, including osteoblast differentiation and matrix mineralization, osteoclast recruitment and cell fusion and osteoblast/osteoclast progenitor cell proliferation. The expression and function of Notch1-4 in the skeleton are distinct and closely depend on the temporal expression at different differentiation stages. This review addresses the current knowledge on Notch signaling in adult bone with emphasis on metabolism, bone regeneration and degenerative skeletal disorders, as well as congenital disorders associated with mutant Notch genes. Moreover, the crosstalk between Notch signaling and other important pathways involved in bone turnover, including Wnt/β-catenin, BMP and RANKL/OPG, are outlined.
Highlights
Notch1, or by the γ-secretase inhibitor DAPT, in a concentration-dependent manner [74]. This effect was reversible in in vitro experiments when cells were infected with a recombinant adenovirus inducing the expression of the Notch ligand Dll1. These results indicate an impact of Notch signaling on BMP9-induced osteogenic factors, especially during the early period of osteogenic differentiation of mesenchymal stem cells (MSC)
Receptors of the Notch family and their signaling play an essential role during the development of the skeleton, as well as in physiology of the bone metabolism and regeneration (Figure 5)
Mutations in genes encoding either the Notch receptors or their ligands lead to severe functional impairment and syndromic diseases
Summary
Four Notch receptors (Notch1-4) have been discovered in vertebrates [4] They are expressed in almost all organs by various cell types and coordinate cell proliferation, differentiation and apoptosis, and cell fate decisions. Differential expression of Notch receptors and ligands has been observed under a variety of physiological and pathological situations, e.g., in inflammatory diseases and cancer [6,7]. In this regard, it has been demonstrated that the Notch pathway plays a pivotal role in the development and metabolism of the skeleton [8]. Notch signaling was reported to influence bone remodeling and regenerative processes after fracture [9,10].
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