Palmitoyl acyltransferase, Zdhhc13, facilitates bone mass acquisition by regulating postnatal epiphyseal development and endochondral ossification: a mouse model.
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 articleSubject
AcyltransferasesAnimals
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
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https://hdl.handle.net/10161/10866Published Version (Please cite this version)
10.1371/journal.pone.0092194Publication 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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Show full item recordScholars@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
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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