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Mechanically induced ca^(2+) oscillations in osteocytes release extracellular vesicles and enhance bone formation

Bone Research 2018年第1期6卷 72-82页

作者： Andrea E.Morrell Genevieve N.Brown Samuel T.Robinson Rachel L.Sattler Andrew D.Baik Gehua Zhen xu cao Lynda F.Bonewald Weiyang Jin lance c.kam.x.edward guo Bone Bioengineering Laboratory Department of Biomedical Engineering Columbia University center for Musculoskeletal Research Department of Orthopaedic Surgery Johns Hopkins University Indiana center for Musculoskeletal Health Indiana University School of Medicine Microscale Biocomplexity Laboratory Department of Biomedical Engineering Columbia University

The vast osteocytic network is believed to orchestrate bone metabolic activity in response to mechanical stimuli through production of sclerostin, RANKL, and osteoprotegerin(OPG). However, the mechanisms of osteocyte mechanotransduction remain poorly understood. We've previously shown that osteocyte mechanosensitivity is encoded through unique intracellular calcium (ca^(2+) ) dynamics. Here, by simultaneously monitoring ca^(2+) and actin dynamics in single cells exposed to fluid shear flow, we detected actin network contractions immediately upon onset of flow-induced ca^(2+) transients, which were facilitated by smooth muscle myosin and further confirmed in native osteocytes ex vivo. Actomyosin contractions have been linked to the secretion of extracellular vesicles(EVs), and our studies demonstrate that mechanical stimulation upregulates EV production in osteocytes through immunostaining for the secretory vesicle marker Lysosomal-associated membrane protein 1(LAMP1) and quantifying EV release in conditioned medium, both of which are blunted when ca^(2+) signaling was inhibited by neomycin. Axial tibia compression was used to induce anabolic bone formation responses in mice, revealing upregulated LAMP1 and expected downregulation of sclerostin in vivo. This load-related increase in LAMP1 expression was inhibited in neomycin-injected mice compared to ***-computed tomography revealed significant load-related increases in both trabecular bone volume fraction and cortical thickness after two weeks of loading, which were blunted by neomycin treatment. In summary, we found mechanical stimulation of osteocytes activates ca^(2+) -dependent contractions and enhances the production and release of EVs containing bone regulatory proteins. Further, blocking ca^(2+) signaling significantly attenuates adaptation to mechanical loading in vivo, suggesting a critical role for ca^(2+) -mediated signaling in bone adaptation.

关键词： OPG conditioned medium ca2+-dependent

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Nature：大规模研究揭示生命所必需的基因

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现代生物医学进展 2016年第31期16卷 I0002-I0003页

作者： Dickinson, Mary E. Flenniken, Ann M. Ji, xiao Teboul, Lydia Wong, Michael D. White, Jacqueline K. Meehan, Terrence F. Weninger, Wolfgang J. Westerberg, Henrik Adissu, Hibret Baker, candice N. Bower, Lynette Brown, James M. caddle, L. Brianna chiani, Francesco clary, Dave cleak, James Daly, Mark J. Denegre, James M. Doe, Brendan Dolan, Mary E. Edie, Sarah M. Fuchs, Helmut Gailus-Durner, Valerie Galli, Antonella Gambadoro, Alessia Gallegos, Juan guo, Shiying Horner, Neil R. Hsu, chih-Wei Johnson, Sara J. Kalaga, Sowmya Keith, lance c. Lanoue, Louise Lawson, Thomas N. Lek, Monkol Mark, Manuel Arschall, Susan M. Mason, Jeremy McElwee, Melissa L. Newbigging, Susan Nutter, Lauryl M. J. Peterson, Kevin A. Ramirez-Solis, Ramiro Rowland, Douglas J. Ryder, edward Samocha, Kaitlin E. Seavitt, John R. Selloum, Mohammed Szoke-Kovacs, Zsombor Tamura, Masaru Trainor, Amanda G. Tudose, Ilinca Wakana, Shigeharu Warren, Jonathan Wendling, Olivia West, David B. Wong, Leeyean Yoshiki, Atsushi MacArthur, Daniel G. Tocchini-Valentini, Glauco P. Gao, xiang Flicek, Paul Bradley, Allan Skarnes, William c. Justice, Monica J. Parkinson, Helen E. Moore, Mark Wells, Sara Braun, Robert E. Svenson, Karen L. de Angelis, Martin Hrabe Herault, Yann Mohun, Tim Mallon, Ann-Marie Henkelman, R. Mark Brown, Steve D. M. Adams, David J. Lloyd, K. c. Kent McKerlie, colin Beaudet, Arthur L. Bucan, Maja Murray, Stephen A. Dept Mol Physiol & Biophys Houston TX 77030 USA Toronto ctr Phenogen Toronto ON M5T 3H7 Canada Mt Sinai Hosp Toronto ON M5G 1X5 Canada Univ Penn Perelman Sch Med Genom & Computat Biol Program Philadelphia PA 19104 USA Med Res council Harwell Mammalian Genet Unit Harwell OX11 0RD Oxon England Mary Lyon ctr Harwell OX11 0RD Oxon England Hosp Sick children Mouse Imaging Ctr Toronto ON M5T 3H7 Canada Wellcome Trust Sanger Inst Wellcome Trust Genome Campus Cambridge CB10 1SA England European Bioinformat Inst European Mol Biol Lab Wellcome Trust Genome Campus Cambridge CB10 1SD England Med Univ Vienna Ctr Anat & Cell Biol A-1090 Vienna Austria Hosp Sick children 555 Univ Ave Toronto ON M5G 1X8 Canada Jackson Lab 600 Main St Bar Harbor ME 04609 USA Univ calif Davis Mouse Biol Program Davis CA 95618 USA Italian Natl Res council cNR Inst Cell Biol & Neurobiol Monterotondo Mouse Clin I-00015 Monterotondo Italy Massachusetts Gen Hosp Analyt & Translat Genet Unit Boston MA 02114 USA Broad Inst MIT & Harvard Program Med & Populat Genet Cambridge MA 02142 USA German Res ctr Environm Hlth Helmholtz Zentrum Munchen Inst Expt Genet D-85764 Neuherberg Germany German Mouse clin D-85764 Neuherberg Germany Baylor coll Med Dept Mol & Human Genet Houston TX 77030 USA Nanjing Univ Nanjing Biomed Res Inst Collaborat Innovat Ctr Genet & Dev SKL Pharmaceut Biotechnol & Model Anim Res Ctr Nanjing 210061 Jiangsu Peoples R China Univ Strasbourg ICS Infrastruct Natl PHENOMIN F-67404 Illkirch Graffenstaden France Univ Strasbourg INSERM CNRS IGBMC F-67404 Illkirch Graffenstaden France RIKEN BioResource Ctr Tsukuba Ibaraki 3050074 Japan childrens Hosp Oakland Res Inst Oakland CA 94609 USA IMPc San Anselmo CA 94960 USA Tech Univ Munich Sch Life Sci Weihenstephan Chair Expt Genet D-81675 Freising Weihenstephan Germany German ctr Diabet Res DZD D-85764 Neuherberg Germany Francis crick Inst Mill Hill Lab Mill Hill London NW1 1AT England Univ Penn Perlman

在哺乳动物基因组中。大约三分之一的基因是生命所必需的。在一项新的研究中，来自美国贝勒医学院等多个机构的研究人员描述了这些基因的大规模发现。以及它将如何影响对哺乳动物发育和人类疾病的理解。相关研究结果在线发表在Nature期... 详细信息

在哺乳动物基因组中。大约三分之一的基因是生命所必需的。在一项新的研究中，来自美国贝勒医学院等多个机构的研究人员描述了这些基因的大规模发现。以及它将如何影响对哺乳动物发育和人类疾病的理解。相关研究结果在线发表在Nature期刊上，论文标题为“High—throughput discovery of novel developmental phenotypes”。

关键词：动物基因组生命哺乳动物研究人员人类疾病医学院

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