Mechanical forces switch blood vessel subtypes to arrest adolescent bone growth
Mechanical forces switch blood vessel subtypes to arrest adolescent bone growth
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DOI：
10.21203/rs.3.rs-120475/v1
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发表时间：
2021-01
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影响因子：
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通讯作者：
M. Löhning;M. Dzamukova;Tobias M. Brunner;J. Miotla‐Zarebska;F. Heinrich;Laura J Brylka;M. Mashreghi;Anjali P. Kusumbe;Ralf Kuehn;T. Schinke;T. Vincent
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文献类型：
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作者：
M. Löhning;M. Dzamukova;Tobias M. Brunner;J. Miotla‐Zarebska;F. Heinrich;Laura J Brylka;M. Mashreghi;Anjali P. Kusumbe;Ralf Kuehn;T. Schinke;T. Vincent
骨生长需要一种专门的、高度血管生成的血管亚型，即所谓的H型血管1，2，为这些血管周围的成骨细胞铺平道路3。在青春期结束时，H型内皮细胞分化为静止的L型内皮细胞，缺乏促进骨生长的能力。到目前为止，关闭H型血管身份并因此阻止青少年骨生长的信号仍然不明确。在这里，我们表明，机械力，与青春期结束时体重增加，触发机械感受器PIEZO 1，从而介导增强生产的激酶FAM 20 C在成骨细胞。FAM20 C磷酸化牙本质基质蛋白1（DMP1）4，以前被认为是骨矿化的关键因素5。这种磷酸化导致成骨细胞分泌DMP1的爆发。细胞外DMP1通过阻止H型内皮细胞尖端细胞上的VEGFR2磷酸化和VEGFR3表达来抑制血管内皮生长因子（VEGF）信号传导。DMP1介导的VEGF抑制将促进骨生长的H型血管转化为静止的L型血管，以阻止骨生长并增强骨矿化。这种分子机制通过细胞外基质蛋白的积累及其对血管亚型的调节将机械力和骨生长的终止联系起来。它为治疗以骨的不适当转换或侵袭为特征的疾病（如骨关节炎、骨质疏松症和骨肉瘤）提供了新的选择。
Bone growth requires a specialised, highly angiogenic blood vessel subtype, so-called type H vessels1,2, which pave the way for osteoblasts surrounding these vessels3. 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)4, previously identified as a key factor in bone mineralization5. 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.