ACVR1(R206H) FOP mutation alters mechanosensing and tissue stiffness during heterotopic ossification.
ACVR1(R206H) FOP mutation alters mechanosensing and tissue stiffness during heterotopic ossification.
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DOI：
10.1091/mbc.e18-05-0311
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发表时间：
2019-01-01
影响因子：
3.3
通讯作者：
Shore EM
中科院分区：
文献类型：
--
作者：
Haupt J;Stanley A;McLeod CM;Cosgrove BD;Culbert AL;Wang L;Mourkioti F;Mauck RL;Shore EM
骨形态发生蛋白(BMP)I型受体ACVR1(ACVR1R206H)突变增强了BMP途径的信号转导，导致罕见的异位(骨外)成骨纤维发育不良进行性骨质疏松症。异位骨化经常发生在损伤后，因为细胞在组织修复过程中异常分化。来自组织微环境的生物力学信号和细胞对这些物理信号的反应，如僵硬和僵硬，是细胞分化的重要决定因素，并受BMP信号的调节。我们使用了Acvr1R206H/+小鼠损伤诱导的异位骨化模型来检查异位骨之前的纤维增殖组织，并确定了修复阶段的病理性僵硬。Acvr1R206H/+细胞对微环境僵硬的反应显示，Acvr1R206H/+细胞不适当地感知其环境，对具有类似于刚性基质上的野生型细胞的铺展形态的软基质以及对正在进行成骨细胞形成的细胞做出反应。RhoA及其下游效应器的激活增加显示了机械信号的增加。成骨因子RUNX2在柔软和坚硬的底物上的核定位暗示了这种细胞命运的易感性。我们的数据支持，Acvr1R206H/+细胞中BMP信号的增加改变了组织微环境，并通过改变对机械刺激的敏感性而导致对组织微环境的误解，从而降低了承诺软骨/成骨细胞系的门槛。
An activating bone morphogenetic proteins (BMP) type I receptor ACVR1 (ACVR1R206H) mutation enhances BMP pathway signaling and causes the rare genetic disorder of heterotopic (extraskeletal) bone formation fibrodysplasia ossificans progressiva. Heterotopic ossification frequently occurs following injury as cells aberrantly differentiate during tissue repair. Biomechanical signals from the tissue microenvironment and cellular responses to these physical cues, such as stiffness and rigidity, are important determinants of cell differentiation and are modulated by BMP signaling. We used an Acvr1R206H/+ mouse model of injury-induced heterotopic ossification to examine the fibroproliferative tissue preceding heterotopic bone and identified pathologic stiffening at this stage of repair. In response to microenvironment stiffness, in vitro assays showed that Acvr1R206H/+ cells inappropriately sense their environment, responding to soft substrates with a spread morphology similar to wild-type cells on stiff substrates and to cells undergoing osteoblastogenesis. Increased activation of RhoA and its downstream effectors demonstrated increased mechanosignaling. Nuclear localization of the pro-osteoblastic factor RUNX2 on soft and stiff substrates suggests a predisposition to this cell fate. Our data support that increased BMP signaling in Acvr1R206H/+ cells alters the tissue microenvironment and results in misinterpretation of the tissue microenvironment through altered sensitivity to mechanical stimuli that lowers the threshold for commitment to chondro/osteogenic lineages.