Dysregulated BMP signaling and enhanced osteogenic differentiation of connective tissue progenitor cells from patients with fibrodysplasia ossificans progressiva (FOP)
Dysregulated BMP signaling and enhanced osteogenic differentiation of connective tissue progenitor cells from patients with fibrodysplasia ossificans progressiva (FOP)
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DOI：
10.1359/jbmr.071030
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发表时间：
2008-03-01
影响因子：
6.2
通讯作者：
Kaplan, Frederick S.
中科院分区：
文献类型：
--
作者：
Billings, Paul C.;Fiori, Jennifer L.;Kaplan, Frederick S.
进行性异位骨化的一种致残性遗传疾病——进行性骨化性纤维发育不良（FOP）的研究，因缺乏容易获取的结缔组织祖细胞而受阻。我们从FOP患者和对照者废弃的乳牙中分离出此类细胞，并发现与对照细胞相比，FOP细胞中骨形态发生蛋白（BMP）信号传导失调且成骨细胞分化迅速。
引言：进行性骨化性纤维发育不良（FOP）是人类进行性异位骨化中最具致残性的疾病，在所有典型受累个体中，是由激活素受体IA（ACVR1）（一种骨形态发生蛋白（BMP）I型受体）的反复杂合错义突变引起的。对FOP的全面理解在一定程度上受到限制，原因是缺乏可用于研究该疾病分子病理学的容易获取的结缔组织祖细胞。
材料和方法：我们从FOP患者和对照者废弃的乳牙中获取结缔组织祖细胞（SHED细胞），并检测这些细胞中的BMP信号传导和成骨分化。
结果：SHED细胞通过SMAD和p38丝裂原活化蛋白激酶（MAPK）途径传递BMP信号，并通过诱导BMP应答基因对BMP4处理作出反应。FOP细胞表现出不依赖配体的BMP信号传导以及对BMP刺激的依赖配体的高反应性。此外，FOP细胞比对照细胞更快地分化为成骨表型。
结论：这是对FOP患者结缔组织祖细胞中BMP信号传导和成骨分化的首次研究。我们的数据有力地支持了BMP信号传导的基础和配体刺激失调，这与对该疾病中突变的ACVR1受体的计算机模拟研究结果一致。这项研究极大地拓展了我们对与这种进行性异位骨化灾难性疾病发病机制相关的祖细胞群中BMP信号传导失调的理解。
The study of FOP, a disabling genetic disorder of progressive heterotopic ossification, is hampered by the lack of readily available connective tissue progenitor cells. We isolated such cells from discarded primary teeth of patients with FOP and controls and discovered dysregulation of BMP signaling and rapid osteoblast differentiation in FOP cells compared with control cells.Introduction: Fibrodysplasia ossificans progressiva (FOP), the most disabling condition of progressive heterotopic ossification in humans, is caused by a recurrent heterozygous missense mutation in activin receptor IA (ACVR1), a bone morphogenetic protein (BMP) type I receptor, in all classically affected individuals. A comprehensive understanding of FOP has been limited, in part, by a lack of readily available connective tissue progenitor cells in which to study the molecular pathology of this disorder.Materials and Methods: We derived connective tissue progenitor cells from discarded primary teeth (SHED cells) of patients with FOP and controls and examined BMP signaling and osteogenic differentiation in these cells.Results: SHED cells transmitted BMP signals through both the SMAD and p38 mitogen-activated protein kinase (MAPK) pathways and responded to BMP4 treatment by inducing BMP responsive genes. FOP cells showed ligand-independent BMP signaling and ligand-dependent hyper-responsiveness to BMP stimulation. Furthermore, FOP cells showed more rapid differentiation to an osteogenic phenotype than control cells.Conclusions: This is the first study of BMP signaling and osteogenic differentiation in connective tissue progenitor cells from patients with FOP. Our data strongly support both basal and ligand-stimulated dysregulation of BMP signaling consistent with in silico studies of the mutant ACVR1 receptor in this condition. This study substantially extends our understanding of dysregulated BMP signaling in a progenitor cell population relevant to the pathogenesis of this catastrophic disorder of progressive ectopic ossification.