title: 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.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: I-Wen
authors.initials: IW
authors.lastname: Song
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Wei-Ru
authors.initials: WR
authors.lastname: Li
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Li-Fen
authors.initials: LF
authors.lastname: Shen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Kai-Ming
authors.initials: KM
authors.lastname: Liu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Jeffrey J Y
authors.initials: JJ
authors.lastname: Yen
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Medicine, Division of Rheumatology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Virginia Byers
authors.initials: VB
authors.lastname: Kraus
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Jer-Yuarn
authors.initials: JY
authors.lastname: Wu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Laboratory for International Alliance on Genomic Research, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: M T Michael
authors.initials: MT
authors.lastname: Lee
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
mesh_terms: D000217:Acyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D015519:Bone Density; D002356:Cartilage / Q000473:pathology* / Q000503:physiopathology*; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D004838:Epiphyses / Q000098:blood supply / Q000254:growth & development* / Q000473:pathology* / Q000503:physiopathology; D018507:Gene Expression Regulation, Developmental; D006132:Growth Plate / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D006984:Hypertrophy; D054878:Lipoylation; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D009154:Mutation / Q000235:genetics; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D011485:Protein Binding; D011859:Radiography; D013347:Subcellular Fractions / Q000201:enzymology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D015675:Osteocalcin; D000217:Acyltransferases; C552301:Zdhhc13 protein, mouse; D053511:Matrix Metalloproteinase 14