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

• Published in: PloS one 2014-03, Vol.9 (3), p.e92194-e92194
• Main Authors: Song, I-Wen, Li, Wei-Ru, Chen, Li-Ying, Shen, Li-Fen, Liu, Kai-Ming, Yen, Jeffrey J Y, Chen, Yi-Ju, Chen, Yu-Ju, Kraus, Virginia Byers, Wu, Jer-Yuarn, Lee, M T Michael, Chen, Yuan-Tsong
• Format: Article
• Language: English
• Subjects: Acyltransferase; Acyltransferases - deficiency; Acyltransferases - genetics; Acyltransferases - metabolism; Alopecia; Amyloidosis; Angiogenesis; Animals; Animals, Newborn; Biocompatibility; Biology and Life Sciences; Biomedical materials; Biotin; Body size; Bone (endochondral); Bone (trabecular); Bone Density; Bone mass; Bone mineral density; Bone turnover; Cancellous bone; Cartilage; Cartilage - pathology; Cartilage - physiopathology; Cell Proliferation; Chondrocytes; Chondrocytes - metabolism; Chondrocytes - pathology; Computed tomography; Endochondral bone; Epiphyses - blood supply; Epiphyses - growth & development; Epiphyses - pathology; Epiphyses - physiopathology; Epiphysis; Ethanol; Gene Expression Regulation, Developmental; Genomes; Glycerol; Growth plate; Growth Plate - pathology; Growth rate; HEK293 Cells; Homeostasis; Humans; Hypertrophy; Immunoprecipitation; Laboratories; Life sciences; Lipoylation; Matrix Metalloproteinase 14 - metabolism; Medicine and Health Sciences; Mice; Models, Animal; Mutagenesis; Mutation; Mutation - genetics; Nonsense mutation; Organ Size; Ossification; Osteoblasts; Osteoblasts - metabolism; Osteocalcin; Osteocalcin - metabolism; Osteogenesis; Osteoporosis; Osteoporosis - diagnostic imaging; Osteoporosis - pathology; Osteoporosis - physiopathology; Palmitic acid; Pathogenesis; Plates (structural members); Protein Binding; Proteins; Radiography; Research and Analysis Methods; Rodents; Signal transduction; Subcellular Fractions - enzymology; Substrates; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0092194

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.