Palmitoyl Acyltransferase, Zdhhc13, Facilitates Bone Mass Acquisition by Regulating Postnatal Epiphyseal Development and Endochondral Ossification: A Mouse Model
Palmitoyl Acyltransferase, Zdhhc13, Facilitates Bone Mass Acquisition by Regulating Postnatal Epiphyseal Development and Endochondral Ossification: A Mouse Model
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DOI：
10.1371/journal.pone.0092194
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发表时间：
2014-03-17
期刊：
影响因子：
3.7
通讯作者：
Chen, Yuan-Tsong
中科院分区：
文献类型：
--
作者：
Song, I-Wen;Li, Wei-Ru;Chen, Yuan-Tsong
ZDHHC13是含有DHHC的棕榈酰转移酶(PATS)家族的成员。它的功能是翻译后通过硫代酯键将16碳棕榈酸酯添加到蛋白质中。我们之前已经证明，携带隐性Zdhc13无义突变导致Zdhc13缺乏的小鼠会患上脱发、淀粉样变性和骨质疏松症。我们的目标是在这种突变的背景下研究小鼠骨质疏松的致病机制。在出生时，Zdhc13 WT小鼠和突变小鼠的体型、骨骼结构和骨小梁相似。突变小鼠在第10天和4周龄时出现生长迟缓和继发性骨化中心形成延迟，生长板结构紊乱，骨质疏松。来自4-20周龄的连续显微CT显示，Zdhc13突变小鼠的骨密度降低。通过免疫共沉淀和酰基生物素交换，确定MT1-MMPs为ZDHHC13的直接底物。在细胞中，MT1-MMP棕榈酰化水平的降低影响了其在亚细胞中的分布，并与软骨细胞和成骨细胞中VEGF和骨钙素的表达减少有关。在Mt1-MMP棕榈酸化的Zdhc13突变小鼠骨痂中，基于免疫组织化学分析，肥大的软骨细胞中的血管内皮生长因子和软骨-骨界面的骨钙素减少。我们的结果表明，Zdhhc13是一种新的出生后骨骼发育和骨量获得的调节因子。据我们所知，这些数据首次表明ZDHHC13介导的MT1-MMP棕榈酰化是骨稳态的关键调节器。这些数据可能为棕榈酰化在人类骨质疏松症发病机制中的作用提供新的见解。
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 acylbiotin 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.