Pigment epithelium-derived factor (PEDF) normalizes matrix defects in iPSCs derived from Osteogenesis imperfecta Type VI
Pigment epithelium-derived factor (PEDF) normalizes matrix defects in iPSCs derived from Osteogenesis imperfecta Type VI
复制标题
DOI：
10.1080/21675511.2016.1212150
复制
发表时间：
2016-01-01
期刊：
影响因子：
--
通讯作者：
Chung, Chuhan
中科院分区：
文献类型：
--
作者：
Belinsky, Glenn S.;Ward, Leanne;Chung, Chuhan
成骨不全(OI)VI型以骨矿化缺陷为特征，导致早期多发骨折。PEDF基因SERPINF1的零突变是OI VI的原因。在OI VI型小鼠模型中，PEDF修复是否能改善骨量和功能此前尚不清楚。在Belinsky等人中，我们提供了PEDF注射增加体内骨量和改善骨功能参数的证据。此外，我们还证明了PEDF暂时抑制Wnt信号以促进成骨细胞分化。在这里，我们证明了从PEDF缺失的患者中产生诱导多能干细胞(IPSCs)为PEDF在调节成骨细胞分泌的细胞外基质蛋白中的作用提供了额外的证据。PEDF缺失的IPSCs在分泌的基质蛋白方面有显著的异常，这是人类OI VI型的一个关键特征，而外源性PEDF使其正常化。最后，我们把我们的最新发现放在PEDF生物学和与其行为有关的发育信号通路的更广泛的背景下。
Osteogenesis imperfecta (OI) Type VI is characterized by a defect in bone mineralization, which results in multiple fractures early in life. Null mutations in the PEDF gene, Serpinf1, are the cause of OI VI. Whether PEDF restoration in a murine model of OI Type VI could improve bone mass and function was previously unknown. In Belinsky et al, we provided evidence that PEDF delivery enhanced bone mass and improved parameters of bone function in vivo. Further, we demonstrated that PEDF temporally inhibits Wnt signaling to enhance osteoblast differentiation. Here, we demonstrate that generation of induced pluripotent stem cells (iPSCs) from a PEDF null patient provides additional evidence for PEDF's role in regulating extracellular matrix proteins secreted from osteoblasts. PEDF null iPSCs have marked abnormalities in secreted matrix proteins, capturing a key feature of human OI Type VI, which were normalized by exogenous PEDF. Lastly, we place our recent findings within the broader context of PEDF biology and the developmental signaling pathways that are implicated in its actions.