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

Maria Dzamukova (), Tobias M. Brunner, Jadwiga Miotla-Zarebska, Frederik Heinrich, Laura Brylka, Mir-Farzin Mashreghi, Anjali Kusumbe, Ralf Kühn, Thorsten Schinke, Tonia L. Vincent and Max Löhning ()
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Maria Dzamukova: Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Centre (DRFZ), a Leibniz Institute
Tobias M. Brunner: Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Centre (DRFZ), a Leibniz Institute
Jadwiga Miotla-Zarebska: Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, University of Oxford
Frederik Heinrich: Therapeutic Gene Regulation, Regine von Ramin Lab Molecular Rheumatology, German Rheumatism Research Centre (DRFZ), a Leibniz Institute
Laura Brylka: University Medical Center Hamburg-Eppendorf
Mir-Farzin Mashreghi: Therapeutic Gene Regulation, Regine von Ramin Lab Molecular Rheumatology, German Rheumatism Research Centre (DRFZ), a Leibniz Institute
Anjali Kusumbe: Tissue and Tumour Microenvironments Group, University of Oxford
Ralf Kühn: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC)
Thorsten Schinke: University Medical Center Hamburg-Eppendorf
Tonia L. Vincent: Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, University of Oxford
Max Löhning: Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Centre (DRFZ), a Leibniz Institute

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30618-8

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