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      The mechanosensitive Piezo1 channel is required for bone formation

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          Abstract

          Mechanical load of the skeleton system is essential for the development, growth, and maintenance of bone. However, the molecular mechanism by which mechanical stimuli are converted into osteogenesis and bone formation remains unclear. Here we report that Piezo1, a bona fide mechanotransducer that is critical for various biological processes, plays a critical role in bone formation. Knockout of Piezo1 in osteoblast lineage cells disrupts the osteogenesis of osteoblasts and severely impairs bone structure and strength. Bone loss that is induced by mechanical unloading is blunted in knockout mice. Intriguingly, simulated microgravity treatment reduced the function of osteoblasts by suppressing the expression of Piezo1. Furthermore, osteoporosis patients show reduced expression of Piezo1, which is closely correlated with osteoblast dysfunction. These data collectively suggest that Piezo1 functions as a key mechanotransducer for conferring mechanosensitivity to osteoblasts and determining mechanical-load-dependent bone formation, and represents a novel therapeutic target for treating osteoporosis or mechanical unloading-induced severe bone loss.

          eLife digest

          The bones in our skeletons are constantly exposed to mechanical forces, including those exerted by our muscles and also Earth’s gravity. These forces normally help osteoblasts, the cells which build new bone tissue, ensure that bones grow correctly and remain strong. Removing mechanical loads from bones, however, disrupts this process, leading to rapid loss of bone tissue. This is why both astronauts in space (where gravity is much weaker) and bed-ridden patients often go on to develop brittle bones.

          To detect and respond to mechanical forces, cells use specialized sensor proteins. One such ‘mechanosensor’ is a protein called Piezo1, which is found on the surface of many different types of cells in our bodies. It helps cells respond to touch, pressure, or stretching of the surrounding tissue. For example, Piezo1 in nerve cells underpins our sense of touch, while in the cells lining our blood vessels it senses the force exerted by blood flow.

          Although osteoblasts clearly respond to mechanical stimuli, exactly how they do so has remained unknown. Sun et al. therefore wanted to find out if Piezo1 also acted as a mechanosensor in osteoblasts, and if so, what role it might play in the loss or formation of bone tissue after changes in the amount of force the bone is exposed to.

          Experiments using mouse cells grown in the laboratory revealed that Piezo1 was present in osteoblasts and did indeed help the cells respond to mechanical impact of being poked by a microscopic probe. Mice that had been genetically engineered to remove Piezo1 from their osteoblasts did not grow properly, appearing stunted in adulthood. In these mice, the bones supporting most of the body’s weight were also shorter and weaker.

          Crucially, putting normal bone cells in a low-gravity simulator – therefore mimicking space flight – or exposing mice to conditions mimicking bed-rest was enough to reduce the level of Piezo1 in osteoblasts. In human patients with osteoporosis, where bones become brittle with age, a decrease in levels of Piezo1 is correlated with increasing bone loss. These results show that Piezo1 is required to make healthy bone tissue, and that its loss is probably involved in the increasing fragility that occurs when mechanical forces applied to bones are reduced.

          This work is an important step towards understanding how our bones are built and maintained. In the future, increasing Piezo1 activity within osteoblasts may lead to treatments for bone loss, whether in hospital patients or astronauts.

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          Most cited references39

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          Piezos are pore-forming subunits of mechanically activated channels

          Mechanotransduction plays a crucial role in physiology. Biological processes including sensing touch and sound waves require yet unidentified cation channels that detect pressure. Mouse piezo1 (mpiezo1) and mpiezo2 induce mechanically activated cationic currents in cells; however, it is unknown if piezos are pore-forming ion channels or modulate ion channels. We show that Drosophila piezo (dpiezo) also induces mechanically activated currents in cells, but through channels with remarkably distinct pore properties including sensitivity to the pore blocker ruthenium red and single channel conductances. mpiezo1 assembles as a ~1.2 million-Dalton tetramer, with no evidence of other proteins in this complex. Finally, purified mpiezo1 reconstituted into asymmetric lipid bilayers and liposomes forms ruthenium red-sensitive ion channels. These data demonstrate that piezos are an evolutionarily conserved ion channel family involved in mechanotransduction.
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            Piezo1, a mechanically activated ion channel, is required for vascular development in mice.

            Mechanosensation is perhaps the last sensory modality not understood at the molecular level. Ion channels that sense mechanical force are postulated to play critical roles in a variety of biological processes including sensing touch/pain (somatosensation), sound (hearing), and shear stress (cardiovascular physiology); however, the identity of these ion channels has remained elusive. We previously identified Piezo1 and Piezo2 as mechanically activated cation channels that are expressed in many mechanosensitive cell types. Here, we show that Piezo1 is expressed in endothelial cells of developing blood vessels in mice. Piezo1-deficient embryos die at midgestation with defects in vascular remodeling, a process critically influenced by blood flow. We demonstrate that Piezo1 is activated by shear stress, the major type of mechanical force experienced by endothelial cells in response to blood flow. Furthermore, loss of Piezo1 in endothelial cells leads to deficits in stress fiber and cellular orientation in response to shear stress, linking Piezo1 mechanotransduction to regulation of cell morphology. These findings highlight an essential role of mammalian Piezo1 in vascular development during embryonic development.
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              Mechanical stretch triggers rapid epithelial cell division through Piezo1

              Despite acting as a barrier for the organs they encase, epithelial cells turnover at some of the fastest rates in the body. Yet, epithelial cell division must be tightly linked to cell death to preserve barrier function and prevent tumour formation. How do the number of dying cells match those dividing to maintain constant numbers? We previously found that when epithelial cells become too crowded, they activate the stretch-activated channel Piezo1 to trigger extrusion of cells that later die 1 . Conversely, what controls epithelial cell division to balance cell death at steady state? Here, we find that cell division occurs in regions of low cell density, where epithelial cells are stretched. By experimentally stretching epithelia, we find that mechanical stretch itself rapidly stimulates cell division through activation of the same Piezo1 channel. To do so, stretch triggers cells paused in early G2 to activate calcium-dependent ERK1/2 phosphorylation that activates cyclin B transcription necessary to drive cells into mitosis. Although both epithelial cell division and cell extrusion require Piezo1 at steady state, the type of mechanical force controls the outcome: stretch induces cell division whereas crowding induces extrusion. How Piezo1-dependent calcium transients activate two opposing processes may depend on where and how Piezo1 is activated since it accumulates in different subcellular sites with increasing cell density. In sparse epithelial regions where cells divide, Piezo1 localizes to the plasma membrane and cytoplasm whereas in dense regions where cells extrude, it forms large cytoplasmic aggregates. Because Piezo1 senses both mechanical crowding and stretch, it may act as a homeostatic sensor to control epithelial cell numbers, triggering extrusion/apoptosis in crowded regions and cell division in sparse regions.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                10 July 2019
                2019
                : 8
                : e47454
                Affiliations
                [1 ]deptState Key Laboratory of Space Medicine Fundamentals and Application China Astronaut Research and Training Center BeijingChina
                [2 ]deptState Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, IDG/McGovern Institute for Brain Research, School of Pharmaceutical Sciences Tsinghua University BeijingChina
                [3 ]The Second Affiliated Hospital of Soochow University SuzhouChina
                Maine Medical Center Research Institute United States
                Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine United States
                Maine Medical Center Research Institute United States
                University of Colorado United States
                Baylor College of Medicine United States
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-5440-3281
                Article
                47454
                10.7554/eLife.47454
                6685704
                31290742
                6ac477fa-3086-4563-908b-b730a24f5406
                © 2019, Sun et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 05 April 2019
                : 06 July 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31630038
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 91740114
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81830061
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31700741
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31825014
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31630090
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002855, Ministry of Science and Technology of the People's Republic of China;
                Award ID: 2016YFA0500402
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002855, Ministry of Science and Technology of the People's Republic of China;
                Award ID: 2015CB910102
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31800994
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81822026
                Award Recipient :
                Funded by: 1226 Project;
                Award ID: AWS16J018
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Cell Biology
                Custom metadata
                Piezo1 functions as a key mechanotransducer for conferring mechanosensitivity to osteoblasts and determining mechanical-load-dependent bone formation, and represents a novel therapeutic target for treating osteoporosis or unloading-induced severe bone loss.

                Life sciences
                piezo1,mechanosensitive ion channel,mechanotransduction,bone formation,unloading,osteoblast,human,mouse

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