Centre de Recherche INSERM 1209, CNRS 5309, Institute for Advanced Bioscience; Université Grenoble Alpes, Grenoble, France.
Centre Hospitalier Universitaire and University of Angers, SNP Plateform, Institute for Biological Health, Transcriptome and Epigenomic, Angers, France.
PLoS One. 2018 Apr 20;13(4):e0196021. doi: 10.1371/journal.pone.0196021. eCollection 2018.
Osteoblast differentiation is a highly regulated process that requires coordinated information from both soluble factors and the extracellular matrix. Among these extracellular stimuli, chemical and physical properties of the matrix are sensed through cell surface receptors such as integrins and transmitted into the nucleus to drive specific gene expression. Here, we showed that the conditional deletion of β1 integrins in the osteo-precursor population severely impacts bone formation and homeostasis both in vivo and in vitro. Mutant mice displayed a severe bone deficit characterized by bone fragility and reduced bone mass. We showed that β1 integrins are required for proper BMP2 dependent signaling at the pre-osteoblastic stage, by positively modulating Smad1/5-dependent transcriptional activity at the nuclear level. The lack of β1 integrins results in a transcription modulation that relies on a cooperative defect with other transcription factors rather than a plain blunted BMP2 response. Our results point to a nuclear modulation of Smad1/5 transcriptional activity by β1 integrins, allowing a tight control of osteoblast differentiation.
成骨细胞分化是一个高度调控的过程，需要来自可溶性因子和细胞外基质的协调信息。在这些细胞外刺激中，基质的化学和物理特性通过细胞表面受体（如整合素）感知，并传递到细胞核内，以驱动特定基因的表达。在这里，我们表明，在成骨前体细胞群体中条件性缺失β1 整合素，会严重影响体内和体外的骨形成和动态平衡。突变小鼠表现出严重的骨缺陷，表现为骨脆弱和骨量减少。我们表明，β1 整合素对于在成骨前体细胞阶段适当的 BMP2 依赖性信号传导是必需的，通过在核水平上正向调节 Smad1/5 依赖性转录活性。缺乏β1 整合素会导致转录调节，这种调节依赖于与其他转录因子的协同缺陷，而不是单纯的 BMP2 反应迟钝。我们的研究结果表明，β1 整合素通过核调节 Smad1/5 转录活性，从而实现对成骨细胞分化的严格控制。
