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. 2021 Jan 29;22(3):1325. doi: 10.3390/ijms22031325

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© 2021 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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Notch-dependent signaling events and signaling crosstalk during the differentiation of MSCs towards osteocytes. Pluripotent MSCs differentiate towards osteoblast progenitors under the influence of PTH, BMP-2 and Wnt-Signaling. The Notch-regulated gene Hey1 inhibits differentiation towards osteoblast progenitors. Notch signaling is enhanced by stimulation of the Hif-1α pathway. Notch activation functions inhibitory on Runx2 and thus on further differentiation of osteoblast progenitors towards osteoblast. The osteoblast entombs itself by synthesizing minerals osteoid. The deposition of minerals and collagens is regulated by Notch [66]. Once the osteoid is mineralized, the osteoblasts are terminally differentiated and become osteocytes. Notch has an indirect influence on osteoclasts via modulation of the RANKL/OPG axis. Notch inhibits OPG, which is an inhibitor of Rank, resulting in an indirect activation of osteoclasts by Notch signaling. Arrows indicate an activation/ induction, and lines with a horizontal bar indicate inactivation/repression.