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Palmitoyl acyltransferase, Zdhhc13, facilitates bone mass acquisition by regulating postnatal epiphyseal development and endochondral ossification: a mouse model.

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Date
2014
Authors
Song, I-Wen
Li, Wei-Ru
Chen, Li-Ying
Shen, Li-Fen
Liu, Kai-Ming
Yen, Jeffrey JY
Chen, Yi-Ju
Chen, Yu-Ju
Kraus, Virginia Byers
Wu, Jer-Yuarn
Lee, MT Michael
Chen, Yuan-Tsong
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(12 total)
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Abstract
ZDHHC13 is a member of DHHC-containing palmitoyl acyltransferases (PATs) family of enzymes. It functions by post-translationally adding 16-carbon palmitate to proteins through a thioester linkage. We have previously shown that mice carrying a recessive Zdhhc13 nonsense mutation causing a Zdhcc13 deficiency develop alopecia, amyloidosis and osteoporosis. Our goal was to investigate the pathogenic mechanism of osteoporosis in the context of this mutation in mice. Body size, skeletal structure and trabecular bone were similar in Zdhhc13 WT and mutant mice at birth. Growth retardation and delayed secondary ossification center formation were first observed at day 10 and at 4 weeks of age, disorganization in growth plate structure and osteoporosis became evident in mutant mice. Serial microCT from 4-20 week-olds revealed that Zdhhc13 mutant mice had reduced bone mineral density. Through co-immunoprecipitation and acyl-biotin exchange, MT1-MMP was identified as a direct substrate of ZDHHC13. In cells, reduction of MT1-MMP palmitoylation affected its subcellular distribution and was associated with decreased VEGF and osteocalcin expression in chondrocytes and osteoblasts. In Zdhhc13 mutant mice epiphysis where MT1-MMP was under palmitoylated, VEGF in hypertrophic chondrocytes and osteocalcin at the cartilage-bone interface were reduced based on immunohistochemical analyses. Our results suggest that Zdhhc13 is a novel regulator of postnatal skeletal development and bone mass acquisition. To our knowledge, these are the first data to suggest that ZDHHC13-mediated MT1-MMP palmitoylation is a key modulator of bone homeostasis. These data may provide novel insights into the role of palmitoylation in the pathogenesis of human osteoporosis.
Type
Journal article
Subject
Acyltransferases
Animals
Animals, Newborn
Bone Density
Cartilage
Cell Proliferation
Chondrocytes
Epiphyses
Gene Expression Regulation, Developmental
Growth Plate
HEK293 Cells
Humans
Hypertrophy
Lipoylation
Matrix Metalloproteinase 14
Mice
Models, Animal
Mutation
Organ Size
Osteoblasts
Osteocalcin
Osteogenesis
Osteoporosis
Protein Binding
Radiography
Subcellular Fractions
Vascular Endothelial Growth Factor A
Permalink
https://hdl.handle.net/10161/10866
Published Version (Please cite this version)
10.1371/journal.pone.0092194
Publication Info
Song, I-Wen; Li, Wei-Ru; Chen, Li-Ying; Shen, Li-Fen; Liu, Kai-Ming; Yen, Jeffrey JY; ... Chen, Yuan-Tsong (2014). Palmitoyl acyltransferase, Zdhhc13, facilitates bone mass acquisition by regulating postnatal epiphyseal development and endochondral ossification: a mouse model. PLoS One, 9(3). pp. e92194. 10.1371/journal.pone.0092194. Retrieved from https://hdl.handle.net/10161/10866.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Yuan-Tsong Chen

Professor Emeritus of Pediatrics
Our overall research interests are in translational research. We aim at translating the promise of genomic medicine into clinical reality. Specific projects at present time include: 1). Identification of novel genes/targets associated with human diseases. This includes susceptibility genes for common multi-factorial diseases and adverse drug reactions. Genetic epidemiology, mouse ENU mutagenesis, bioinformatics and proteomics are some approaches that we use in identif
Kraus

Virginia Byers Kraus

Mary Bernheim Distinguished Professor of Medicine
My special area of expertise is as a clinician scientist investigating osteoarthritis. Osteoarthritis is the most common form of joint disease in man and its incidence increases with age. It is a problem of increasing concern to the medical community due to the increasing longevity of the population. Trained as a molecular biologist and a Rheumatologist, I endeavor to study this disease from bedside to bench. The work in this laboratory focuses on osteoarthritis and deals w
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