Mechanical forces couple bone matrix mineralization with inhibition of angiogenesis to limit adolescent bone growth.
Mechanical forces couple bone matrix mineralization with inhibition of angiogenesis to limit adolescent bone growth.
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机械力将骨基质矿化与血管生成抑制结合起来，以限制青少年骨骼生长。
DOI：
10.1038/s41467-022-30618-8
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发表时间：
2022-06-01
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
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，它为这些血管周围的成骨细胞铺平了道路。在青春期结束时，H型血管分化为静止的L型内皮细胞，缺乏促进骨生长的能力。到目前为止，关闭H型血管身份并因此限制青少年骨骼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是分泌型磷酸化蛋白质组的主要激酶，磷酸化牙本质基质蛋白1，以前被认为是骨矿化的关键因素。于是，牙本质基质蛋白1以爆发样的方式从成骨细胞分泌。细胞外牙本质基质蛋白1通过阻止血管内皮生长因子受体2磷酸化抑制血管内皮生长因子信号传导。因此，分泌的牙本质基质蛋白1将H型血管转化为L型，以限制骨生长活性并增强骨矿化。发现的机制可能为治疗以骨和血管异常活动为特征的疾病（如骨关节炎、骨质疏松症和骨肉瘤）提供新的选择。这项研究表明，机械力触发成骨细胞分泌细胞外基质蛋白质牙本质基质蛋白1。这将促进骨骼生长的血管转化为静止亚型，以限制青春期结束时的骨骼生长。
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. The study shows that mechanical forces trigger secretion of the extracellular matrix protein dentin matrix protein 1 from osteoblasts. This transforms bone growth-promoting blood vessels into a quiescent subtype to limit bone growth at the end of adolescence.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
30.8
作者：
Lorenz-Depiereux, Bettina;Bastepe, Murat;Strom, Tim M.
通讯作者：
Strom, Tim M.
影响因子：
4.1
作者：
Keyak, J. H.;Koyama, A. K.;Lang, T. F.
通讯作者：
Lang, T. F.
影响因子：
7.6
作者：
Feng, JQ;Huang, H;Mishina, Y
通讯作者：
Mishina, Y
影响因子：
2.6
作者：
Maes, C;Carmeliet, P;Carmeliet, G
通讯作者：
Carmeliet, G