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Mechanical forces switch blood vessel subtypes to arrest adolescent bone growth

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Title:Mechanical forces switch blood vessel subtypes to arrest adolescent bone growth
Creators Name:Dzamukova, M. and Brunner, T.M. and Miotla-Zarebska, J. and Heinrich, F. and Brylka, L. and Mashreghi, M.F. and Kusumbe, A. and Kühn, R. and Schinke, T. and Vincent, T. and Löhning, M.
Abstract:Bone growth requires a specialised, highly angiogenic blood vessel subtype, so-called type H vessels, which pave the way for osteoblasts surrounding these vessels. At the end of adolescence, type H endothelial cells differentiate into quiescent type L endothelium lacking the capacity to promote bone growth. Until now, the signals that switch off type H vessel identity and thus arrest adolescent bone growth have remained ill defined. Here we show that mechanical forces, associated with increased body weight at the end of adolescence, trigger the mechanoreceptor PIEZO1 and thereby mediate enhanced production of the kinase FAM20C in osteoblasts. FAM20C phosphorylates dentin matrix protein 1 (DMP1), previously identified as a key factor in bone mineralization. This phosphorylation elicits a burst in DMP1 secretion from osteoblasts. Extracellular DMP1 inhibits vascular endothelial growth factor (VEGF) signalling by preventing VEGFR2 phosphorylation and VEGFR3 expression on the tip cells of type H endothelium. DMP1-mediated VEGF inhibition transforms bone growth-promoting type H vessels into quiescent type L vasculature to arrest bone growth and enhance bone mineralization. This molecular mechanism links mechanical forces and the termination of bone growth via accumulation of an extracellular matrix protein and its regulation of vascular subtypes. It suggests new options for the treatment of diseases characterised by inappropriate turnover or invasion of bone such as osteoarthritis, osteoporosis and osteosarcoma.
Keywords:Bone Growth, Vessels, Animals, Mice
Source:Research Square
Title of Book:Mechanical forces switch blood vessel subtypes to arrest adolescent bone growth
Publisher:Research Square
Article Number:rs.3.rs-120475
Date:12 January 2021
Official Publication:https://doi.org/10.21203/rs.3.rs-120475/v1
Related to:
https://edoc.mdc-berlin.de/21692/Final version

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