Mechanical forces couple bone matrix mineralization with inhibition of angiogenesis to limit adolescent bone growth

Nat Commun. 2022 Jun 1;13(1):3059. doi: 10.1038/s41467-022-30618-8.

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 vessels 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 limit 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, the major kinase of the secreted phosphoproteome, phosphorylates dentin matrix protein 1, previously identified as a key factor in bone mineralization. Thereupon, dentin matrix protein 1 is secreted from osteoblasts in a burst-like manner. Extracellular dentin matrix protein 1 inhibits vascular endothelial growth factor signalling by preventing phosphorylation of vascular endothelial growth factor receptor 2. Hence, secreted dentin matrix protein 1 transforms type H vessels into type L to limit bone growth activity and enhance bone mineralization. The discovered mechanism may suggest new options for the treatment of diseases characterised by aberrant activity of bone and vessels such as osteoarthritis, osteoporosis and osteosarcoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Bone Development
  • Bone Matrix
  • Calcification, Physiologic*
  • Extracellular Matrix Proteins
  • Humans
  • Ion Channels
  • Morphogenesis
  • Neovascularization, Physiologic*
  • Phosphoproteins
  • Stress, Mechanical*
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-2

Substances

  • DMP1 protein, human
  • Extracellular Matrix Proteins
  • Ion Channels
  • PIEZO1 protein, human
  • Phosphoproteins
  • Vascular Endothelial Growth Factor A
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2