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ATP6V1H Deficiency Impairs Bone Development through Activation of MMP9 and MMP13
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نویسنده
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zhang y. ,huang h. ,zhao g. ,yokoyama t. ,vega h. ,huang y. ,sood r. ,bishop k. ,maduro v. ,accardi j. ,toro c. ,boerkoel c.f. ,lyons k. ,gahl w.a. ,duan x. ,malicdan m.c.v. ,lin s.
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منبع
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plos genetics - 2017 - دوره : 13 - شماره : 2
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چکیده
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Atp6v1h is a component of a large protein complex with vacuolar atpase (v-atpase) activity. we identified two generations of individuals in which short stature and osteoporosis co-segregated with a mutation in atp6v1h. since v-atpases are highly conserved between human and zebrafish,we generated loss-of-function mutants in atp6v1h in zebrafish through crispr/cas9-mediated gene knockout. homozygous mutant atp6v1h zebrafish exhibited a severe reduction in the number of mature calcified bone cells and a dramatic increase in the expression of mmp9 and mmp13. heterozygous adults showed curved vertebra that lack calcified centrum structure and reduced bone mass and density. treatment of mutant embryos with small molecule inhibitors of mmp9 and mmp13 significantly restored bone mass in the atp6v1h mutants. these studies have uncovered a new,atp6v1h-mediated pathway that regulates bone formation,and defines a new mechanism of disease that leads to bone loss. we propose that mmp9/mmp13 could be therapeutic targets for patients with this rare genetic disease. © 2017 public library of science. all rights reserved.
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آدرس
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laboratory of chemical genomics,school of chemical biology and biotechnology,peking university shenzhen graduate school,shenzhen,china,department of molecular,cell,and developmental biology,university of california los angeles,los angeles,ca, United States, laboratory of chemical genomics,school of chemical biology and biotechnology,peking university shenzhen graduate school,shenzhen, China, department of molecular,cell,and developmental biology,university of california los angeles,los angeles,ca,united states,department of orthopaedic surgery and orthopaedic institute for children,david geffen school of medicine,university of california,los angeles,ca, United States, medical genetics branch,national human genome research institute,nih,bethesda,md, United States, nih undiagnosed diseases program,common fund,office of the director,nih and national human genome research institute,nih,bethesda,md, United States, nih undiagnosed diseases program,common fund,office of the director,nih and national human genome research institute,nih,bethesda,md, United States, zebrafish core,translational and functional genomics branch,national human genome research institute/nih,bethesda,md, United States, zebrafish core,translational and functional genomics branch,national human genome research institute/nih,bethesda,md, United States, nih undiagnosed diseases program,common fund,office of the director,nih and national human genome research institute,nih,bethesda,md, United States, nih undiagnosed diseases program,common fund,office of the director,nih and national human genome research institute,nih,bethesda,md, United States, nih undiagnosed diseases program,common fund,office of the director,nih and national human genome research institute,nih,bethesda,md, United States, nih undiagnosed diseases program,common fund,office of the director,nih and national human genome research institute,nih,bethesda,md, United States, department of molecular,cell,and developmental biology,university of california los angeles,los angeles,ca,united states,department of orthopaedic surgery and orthopaedic institute for children,david geffen school of medicine,university of california,los angeles,ca, United States, medical genetics branch,national human genome research institute,nih,bethesda,md,united states,nih undiagnosed diseases program,common fund,office of the director,nih and national human genome research institute,nih,bethesda,md,united states,office of the clinical director,national human genome research institute/nih,bethesda,md, United States, state key laboratory of military stomatology,national clinical research center for oral diseases,shaanxi key laboratory of oral diseases,department of oral biology,clinic of oral rare and genetic diseases,school of stomatology,the fourth military medical university,xi’an, China, medical genetics branch,national human genome research institute,nih,bethesda,md,united states,nih undiagnosed diseases program,common fund,office of the director,nih and national human genome research institute,nih,bethesda,md,united states,office of the clinical director,national human genome research institute/nih,bethesda,md, United States, department of molecular,cell,and developmental biology,university of california los angeles,los angeles,ca, United States
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Authors
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