ATP6V1H Deficiency Impairs Bone Development through Activation of MMP9 and MMP13.
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.
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, California, United States of America.
Yihan
Y
Zhang
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen China.
Haigen
H
Huang
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California, United States of America.|Department of Orthopaedic Surgery and Orthopaedic Institute for Children, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.
Gexin
G
Zhao
Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
Tadafumi
T
Yokoyama
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
Hugo
0000-0002-6072-8461
H
Vega
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
Yan
Y
Huang
Zebrafish core, Translational and Functional Genomics Branch, National Human Genome Research Institute/NIH, Bethesda, Maryland, United States of America.
Raman
0000-0001-5565-662X
R
Sood
Zebrafish core, Translational and Functional Genomics Branch, National Human Genome Research Institute/NIH, Bethesda, Maryland, United States of America.
Kevin
K
Bishop
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
Valerie
V
Maduro
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
John
J
Accardi
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
Camilo
C
Toro
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
Cornelius F
CF
Boerkoel
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California, United States of America.|Department of Orthopaedic Surgery and Orthopaedic Institute for Children, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.
Karen
0000-0001-9420-5813
K
Lyons
Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.|NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.|Office of the Clinical Director, National Human Genome Research Institute/NIH, Bethesda, Maryland, United States of America.
William A
WA
Gahl
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.
Xiaohong
X
Duan
Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.|NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.|Office of the Clinical Director, National Human Genome Research Institute/NIH, Bethesda, Maryland, United States of America.
May Christine V
MC
Malicdan
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California, United States of America.
Shuo
S
Lin
D000328:Adult; D000818:Animals; D015519:Bone Density / Q000235:genetics; D001846:Bone Development / Q000235:genetics*; D064113:CRISPR-Cas Systems; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D009154:Mutation; D010024:Osteoporosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D025262:Vacuolar Proton-Translocating ATPases / Q000172:deficiency / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development
D053509:Matrix Metalloproteinase 13; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C567969:ATP6V1H protein, human; D025262:Vacuolar Proton-Translocating ATPases