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.

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Published Version (Please cite this version)

10.1371/journal.pone.0092194

Publication Info

Song, I-Wen, Wei-Ru Li, Li-Ying Chen, Li-Fen Shen, Kai-Ming Liu, Jeffrey JY Yen, Yi-Ju Chen, Yu-Ju Chen, et al. (2014). Palmitoyl acyltransferase, Zdhhc13, facilitates bone mass acquisition by regulating postnatal epiphyseal development and endochondral ossification: a mouse model. PLoS One, 9(3). p. e92194. 10.1371/journal.pone.0092194 Retrieved from https://hdl.handle.net/10161/10866.

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Kraus

Virginia Byers Kraus

Mary Bernheim Distinguished Professor of Medicine

Virginia Byers Kraus, MD, PhD, is the Mary Bernheim Distinguished Professor of Medicine, Professor of Orthopaedic Surgery, Professor of Pathology and a faculty member of the Duke Molecular Physiology Institute in the Duke University School of Medicine. She is a practicing Rheumatologist with over 30 years’ experience in translational musculoskeletal research focusing on osteoarthritis, the most common of all arthritides. She trained at Brown University (ScB 1979), Duke University (MD 1982, PhD 1993) and the Duke University School of Medicine (Residency in Internal Medicine and Fellowship in Rheumatology). Her career has focused on elucidating osteoarthritis pathogenesis and translational research into the discovery and validation of biomarkers for early osteoarthritis detection, prediction of progression, monitoring of disease status, and facilitation of therapeutic developments. She is co-PI of the Foundation for NIH Biomarkers Consortium Osteoarthritis project. Trained as a molecular biologist and a Rheumatologist, she endeavors to study disease from bedside to bench.

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 identification of novel genes associated with the human disease. Genetic markers associated with drug-induced Stevens-Johnson syndrome and other adverse drug reactions have been identified. Prospective studies are in progress to assess the utilization of these markers to prevent the adverse drug reactions. A systematic, genome-wide, phenotype-driven mutagenesis program for gene function studies in the mouse have resulted in the identification of several mouse models of human genetic metabolic diseases. We will continue our research along these lines to identify more novel disease genes/ targets and to increase our understanding of the diseases.

2). Genetics and molecular mechanisms of Stevens-Johnson syndrome. With the identification of HLA-B allele strongly linked to the genetic susceptibility to the drug-induced Stevens-Johnson syndrome, we are investigating how the specific HLA allele mediated the cell toxicity in causing disseminated keratinocyte death.

3). Functional characterization of a novel glucose transporter and its role in diabetes mellitus. We cloned a novel glucose transporter (Glu 10), which is highly expressed in pancreas and liver and is located on a region of a chromosome where a diabetes mellitus type II locus has been mapped. We are currently investigating its role in diabetes by studying mouse models carrying the GLU10 mutations and by direct genetic association study of human patients affected with diabetes.

4). Enzyme and gene therapy and targeting mechanisms of Pompe disease.
Pompe disease is a fatal genetic muscle disorder. As enzyme replacement therapy for Pompe disease moves into clinical reality the fundamental question of how the enzyme targets the heart and skeletal muscle and why some patients respond better than others remain unanswered. We have generated tissue-specific MPR300 knockout mouse model and other animal models to help answer these questions.


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