Loss of Smad4 in the scleraxis cell lineage results in postnatal joint contracture.
Loss of Smad4 in the scleraxis cell lineage results in postnatal joint contracture.
复制标题
Smad 4在巩膜轴细胞谱系中的缺失导致出生后关节挛缩。
DOI：
10.1016/j.ydbio.2020.11.006
复制
发表时间：
2021-03
影响因子：
2.7
通讯作者：
Schweitzer, Ronen
中科院分区：
文献类型：
--
作者：
Schlesinger, Saundra Y.;Seo, Seongkyung;Pryce, Brian A.;Tufa, Sara F.;Keene, Douglas R.;Huang, Alice H.;Schweitzer, Ronen
肌肉骨骼系统的生长需要骨骼、肌肉和肌腱在发育过程中的精确协调。肌肉-肌腱单位相对于骨生长的伸长不足导致关节挛缩，其特征在于关节活动范围减少或完全丧失。在这里，我们建立了一个新的小鼠模型关节挛缩靶向Smad 4的肌腱细胞系中使用Scleraxis-Cre（ScxCre）的删除。Smad 4ScxCre突变体在出生后不久就会发生关节挛缩。挛缩的方向是随机的，严重程度随着年龄的增长而增加。Smad 4ScxCre突变肌腱表现出稳定的细胞减少和细胞外基质体积的逐步减少。胶原纤维直径减少Smad 4ScxCre突变体，表明Smad 4信号在调节基质积累的作用。虽然ScxCre在软骨和肌肉中也有零星的活性，但我们证明了Smad 4在肌腱中的损失对关节挛缩的发展至关重要。在Smad 2;3ScxCre突变体中破坏典型的TGFβ-途径不会导致关节挛缩。相反，通过靶向BMP受体（Alk 3ScxCre/Alk 6 null）破坏BMP途径概括了Smad 4ScxCre挛缩表型的许多特征，表明Smad 4ScxCre突变体中的关节挛缩是由BMP信号传导的破坏引起的。总之，这些结果建立了小鼠出生后关节挛缩模型和BMP信号在肌腱伸长和细胞外基质积累中的作用。
Growth of the musculoskeletal system requires precise coordination between bone, muscle, and tendon during development. Insufficient elongation of the muscle-tendon unit relative to bone growth results in joint contracture, a condition characterized by reduction or complete loss of joint range of motion. Here we establish a novel murine model of joint contracture by targeting Smad4 for deletion in the tendon cell lineage using Scleraxis-Cre (ScxCre). Smad4ScxCre mutants develop a joint contracture shortly after birth. The contracture is stochastic in direction and increases in severity with age. Smad4ScxCre mutant tendons exhibited a stable reduction in cellularity and a progressive reduction in extracellular matrix volume. Collagen fibril diameters were reduced in the Smad4ScxCre mutants, suggesting a role for Smad4 signaling in the regulation of matrix accumulation. Although ScxCre also has sporadic activity in both cartilage and muscle, we demonstrate an essential role for Smad4 loss in tendons for the development of joint contractures. Disrupting the canonical TGFβ-pathway in Smad2;3ScxCre mutants did not result in joint contractures. Conversely, disrupting the BMP pathway by targeting BMP receptors (Alk3ScxCre/Alk6null) recapitulated many features of the Smad4ScxCre contracture phenotype, suggesting that joint contracture in Smad4ScxCre mutants is caused by disruption of BMP signaling. Overall, these results establish a model of murine postnatal joint contracture and a role for BMP signaling in tendon elongation and extracellular matrix accumulation.
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影响因子：
4.8
作者：
Lejard, Veronique;Brideau, Gaelle;Rossert, Jerome
通讯作者：
Rossert, Jerome
影响因子：
4.6
作者：
Howell K;Chien C;Bell R;Laudier D;Tufa SF;Keene DR;Andarawis-Puri N;Huang AH
通讯作者：
Huang AH
DOI：
10.1034/j.1600-0838.2000.010006312.x
发表时间：
2000-12-01
影响因子：
4.1
作者：
Kannus, P
通讯作者：
Kannus, P
DOI：
10.1073/pnas.1609571113
发表时间：
2016-10-11
影响因子：
11.1
作者：
Ishikawa, Yoshihiro;Ito, Shinya;Bachinger, Hans Peter
通讯作者：
Bachinger, Hans Peter
影响因子：
2.4
作者：
Kjær, M;Magnusson, P;Langberg, H
通讯作者：
Langberg, H