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

TY - JOUR

T1 - Mechanical forces couple bone matrix mineralization with inhibition of angiogenesis to limit adolescent bone growth

AU - Dzamukova, Maria

AU - Brunner, Tobias M

AU - Miotla-Zarebska, Jadwiga

AU - Heinrich, Frederik

AU - Brylka, Laura

AU - Mashreghi, Mir-Farzin

AU - Kusumbe, Anjali

AU - Kühn, Ralf

AU - Schinke, Thorsten

AU - Vincent, Tonia L

AU - Löhning, Max

N1 - © 2022. The Author(s).

PY - 2022/6/1

Y1 - 2022/6/1

N2 - 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.

AB - 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.

KW - Adolescent

KW - Bone Development

KW - Bone Matrix

KW - Calcification, Physiologic

KW - Extracellular Matrix Proteins

KW - Humans

KW - Ion Channels

KW - Morphogenesis

KW - Neovascularization, Physiologic

KW - Phosphoproteins

KW - Stress, Mechanical

KW - Vascular Endothelial Growth Factor A

KW - Vascular Endothelial Growth Factor Receptor-2

U2 - 10.1038/s41467-022-30618-8

DO - 10.1038/s41467-022-30618-8

M3 - SCORING: Journal article

C2 - 35650194

VL - 13

SP - 3059

JO - NAT COMMUN

JF - NAT COMMUN

SN - 2041-1723

IS - 1

ER -