Notch Signaling in Osteogenesis, Osteoclastogenesis, and Angiogenesis

Abstract

Skeletal tissue development and regeneration in mammals are intricate, multistep, and highly regulated processes. Various signaling pathways have been implicated in the regulation of these processes, including Notch. Notch signaling is a highly conserved, intercellular signaling pathway that regulates cell proliferation and differentiation, determines cell fate decision, and participates in cellular process in embryonic and adult tissue. Here, we review recent data showing the regulation of Notch signaling in osteogenesis, osteoclastogenesis, and angiogenesis. These processes are cell-context-dependent via direct or indirect mechanisms. Furthermore, Notch signaling may be highly beneficial for efficient coupling of osteogenesis and angiogenesis for tissue engineering and skeletal repair, which is critical to develop clinically therapeutic options.

Figure 1

Notch signaling in bone tissue development. Notch signaling has dual effects on osteogenesis and osteoclastogenesis. Notch signaling activation not only enhances osteogenic differentiation and the bone mineralization process, but also inhibits the osteogenesis by suppressing Wnt/β-catenin signaling. Meanwhile, Notch signaling inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) can enhance the osteogenesis process. Furthermore, Notch activation in osteocytes can suppress bone resorption and increase bone volume by reducing sclerostin (Sost) and dickkopf WNT signaling pathway inhibitor 1 (Dkk1), as well as up-regulation of Wnt signaling. Notch1–3 deficiency directly promotes osteoclastic differentiation, and Notch1 deficiency can promote this process indirectly by decreasing the osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) ratio. The Notch1/Jagged1 axis suppresses osteoclastogenesis, whereas the Notch2/Delta-like (Dll) 1 axis has the opposite effect. Notch activation has a negative effect of osteoclast formation by strongly inhibiting the macrophage colony-stimulating factor (M-CSF).

Figure 2

Notch effect on angiogenesis. Delta-like (Dll) 4 negatively regulates vascular endothelial growth factor (VEGF)-mediated angiogenesis, while Jagged1 is a proangiogenic regulator that antagonizes Dll4-mediated Notch signaling in angiogenesis. Notch intracellular domain (NICD1) enhances bone morphogenetic protein (BMP)-induced angiogenesis.