Acromelic dysplasias: how rare musculoskeletal disorders reveal biological functions of extracellular matrix proteins.
Acromelic dysplasias: how rare musculoskeletal disorders reveal biological functions of extracellular matrix proteins.
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DOI：
10.1111/nyas.14465
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发表时间：
2021-04
影响因子：
5.2
通讯作者：
Hubmacher D
中科院分区：
文献类型：
--
作者：
Stanley S;Balic Z;Hubmacher D
肢端发育不良是一组罕见的肌肉骨骼疾病，共同表现为身材矮小、假性肌型、关节僵硬和皮肤紧绷。顶端发育不良是由编码分泌细胞外基质蛋白的基因(FBN1、ADAMTSL2、ADAMTS10、ADAMTS17、LTBP2和LTBP3)以及Smad4(转化生长因子-β信号的细胞内辅助调节因子)突变引起的。肢端发育不良患者共有的肌肉骨骼表现表明，这些蛋白在生物途径上相互协作，但也在肢端发育不良组的个别疾病中所影响的特定组织中发挥不同的作用。此外，大多数受影响的蛋白质直接与细胞外基质中的纤维素微纤维相互作用，并与转化生长因子-β信号的调节有关。与最近开发的针对受影响基因的敲除小鼠模型一起，对这些蛋白质如何调节肌肉骨骼发育和体内平衡的分子机制出现了新的见解。在这里，我们总结了目前的知识，强调了组成肢端发育不良的不同疾病的致病机制，并提供了一个新的生物作用的个别蛋白的概述。最后，我们开发了一个概念模型，说明这些蛋白质如何相互作用，并在肌肉骨骼系统的结缔组织中的纤维蛋白微纤维上形成“肢端发育不良复合体”。
Acromelic dysplasias are a group of rare musculoskeletal disorders that collectively present with short stature, pseudomuscular build, stiff joints, and tight skin. Acromelic dysplasias are caused by mutations in genes (FBN1, ADAMTSL2, ADAMTS10, ADAMTS17, LTBP2, and LTBP3) that encode secreted extracellular matrix proteins, and in SMAD4, an intracellular coregulator of transforming growth factor-β (TGF-β) signaling. The shared musculoskeletal presentations in acromelic dysplasias suggest that these proteins cooperate in a biological pathway, but also fulfill distinct roles in specific tissues that are affectedin individual disorders of the acromelic dysplasia group. In addition, most of the affected proteins directly interact with fibrillin microfibrils in the extracellular matrix and have been linked to the regulation of TGF-β signaling. Together with recently developed knockout mouse models targeting the affected genes, novel insights into molecular mechanisms of how these proteins regulate musculoskeletal development and homeostasis have emerged. Here, we summarize the current knowledge highlighting pathogenic mechanisms of the different disorders that compose acromelic dysplasias and provide an overview of the emerging biological roles of the individual proteins that are compromised. Finally, we develop a conceptual model of how these proteins may interact and form an “acromelic dysplasia complex” on fibrillin microfibrils in connective tissues of the musculoskeletal system.
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潜在TGF-β结合蛋白(Ltbp)-3缺失小鼠的骨异常表明Ltbp-3在调节TGF-β生物利用度中的作用。
DOI：
10.1083/jcb.200111080
发表时间：
2002-01-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Dabovic B;Chen Y;Colarossi C;Obata H;Zambuto L;Perle MA;Rifkin DB
通讯作者：
Rifkin DB
影响因子：
4.6
作者：
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通讯作者：
Woods, Michael O.
影响因子：
3.5
作者：
Aubart, Melodie;Gross, Marie-Sylvie;Stheneur, Chantal
通讯作者：
Stheneur, Chantal
影响因子：
3.7
作者：
Bader, Hannah L.;Ruhe, Alison L.;Neff, Mark W.
通讯作者：
Neff, Mark W.
影响因子：
9.8
作者：
Dagoneau, N;Benoist-Lasselin, C;Cormier-Daire, V
通讯作者：
Cormier-Daire, V