Fibrillin-1 deficiency in the outer perichondrium causes longitudinal bone overgrowth in mice with Marfan syndrome.
Fibrillin-1 deficiency in the outer perichondrium causes longitudinal bone overgrowth in mice with Marfan syndrome.
复制标题
外软骨膜中的 Fibrillin-1 缺乏会导致马凡氏综合征小鼠纵向骨过度生长。
DOI：
10.1093/hmg/ddac107
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发表时间：
2022
影响因子：
3.5
通讯作者：
Ramirez,Francesco
中科院分区：
文献类型：
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作者：
Sedes,Lauriane;Wondimu,Elisa;Crockett,Brittany;Hansen,Jens;Cantalupo,Anna;Asano,Keiichi;Iyengar,Ravi;Rifkin,DanielB;Smaldone,Silvia;Ramirez,Francesco
不成比例的身高是马凡综合征(MFS)最明显的表现，这是一种由细胞外蛋白和转化生长因子β调节剂纤维蛋白-1突变引起的多系统疾病。与心血管表现不同的是，很少有人致力于揭示MFS中长骨过度生长的分子机制。通过结合Cre-LoxPrebition系统和跖骨培养，我们在这里确定了软骨膜的外层是导致MFS小鼠长骨过度生长的组织。对纤维素1缺乏的软骨膜中差异表达基因的分析表明，转化生长因子β信号的缺失可能会影响邻近骨盆生长板(GP)的软骨形成。免疫组织化学显示，外软骨膜纤维蛋白-1缺乏与潜在的转化生长因子β结合蛋白(LTBP)-3和BMP-4的积聚减少以及磷酸化(激活)的Smad2水平降低有关。与这些发现一致的是，突变的跖骨在体外生长的时间比野生型更长，释放的转化生长因子β更少。此外，重组转化生长因子β-1的加入使突变的跖骨的线性生长正常化。我们认为这是由于LTBP-3和LTBP-4在外软骨膜纤维蛋白-1缺乏的基质中的滞留减少，导致局部转化生长因子β信号减少和远端GP分化不良所致。
A disproportionate tall stature is the most evident manifestation in Marfan syndrome (MFS), a multisystem condition caused by mutations in the extracellular protein and TGFβ modulator, fibrillin-1. Unlike cardiovascular manifestations, there has been little effort devoted to unravel the molecular mechanism responsible for long bone overgrowth in MFS. By combining theCre-LoxPrecombination system with metatarsal bone cultures, here we identify the outer layer of the perichondrium as the tissue responsible for long bone overgrowth in MFS mice. Analyses of differentially expressed genes in the fibrillin-1-deficient perichondrium predicted that loss of TGFβ signaling may influence chondrogenesis in the neighboring epiphyseal growth plate (GP). Immunohistochemistry revealed that fibrillin-1 deficiency in the outer perichondrium is associated with decreased accumulation of latent TGFβ-binding proteins (LTBPs)-3 and -4, and reduced levels of phosphorylated (activated) Smad2. Consistent with these findings, mutant metatarsal bones grownin vitrowere longer and released less TGFβ than the wild-type counterparts. Moreover, addition of recombinant TGFβ1 normalized linear growth of mutant metatarsal bones. We conclude that longitudinal bone overgrowth in MFS is accounted for by diminished sequestration of LTBP-3 and LTBP-4 into the fibrillin-1-deficient matrix of the outer perichondrium, which results in less TGFβ signaling locally and improper GP differentiation distally.