进行性骨化性纤维发育不良（FOP）患者结缔组织祖细胞的骨形态发生蛋白（BMP）信号失调及成骨分化增强。
Dysregulated BMP signaling and enhanced osteogenic differentiation of connective tissue progenitor cells from patients with fibrodysplasia ossificans progressiva (FOP).
作者信息
Billings Paul C, Fiori Jennifer L, Bentwood Jennifer L, O'Connell Michael P, Jiao Xiangyang, Nussbaum Burton, Caron Robert J, Shore Eileen M, Kaplan Frederick S
机构信息
The Center for Research in FOP and Related Disorders, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
出版信息
J Bone Miner Res. 2008 Mar;23(3):305-13. doi: 10.1359/jbmr.071030.
UNLABELLED
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.
未标记
进行性骨化性纤维发育不良（FOP）是一种导致残疾的进行性异位骨化的遗传性疾病，由于缺乏易于获得的结缔组织祖细胞，对其研究受到阻碍。我们从FOP患者和对照者废弃的乳牙中分离出此类细胞，发现与对照细胞相比，FOP细胞中骨形态发生蛋白（BMP）信号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最致残的病症，在所有典型受影响个体中，由激活素受体IA（ACVR1）（一种I型骨形态发生蛋白（BMP）受体）中的复发性杂合错义突变引起。对FOP的全面理解在一定程度上受到限制，部分原因是缺乏易于获得的结缔组织祖细胞来研究这种疾病的分子病理学。
材料与方法
我们从FOP患者和对照者废弃的乳牙（脱落乳牙干细胞）中获得结缔组织祖细胞，并检测这些细胞中的BMP信号和成骨分化。
结果
脱落乳牙干细胞通过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反应基因对BMP4处理作出反应。FOP细胞表现出不依赖配体的BMP信号和对BMP刺激的配体依赖性高反应性。此外，FOP细胞比对照细胞表现出更快地分化为成骨表型。
结论
这是首次对FOP患者结缔组织祖细胞中的BMP信号和成骨分化进行研究。我们的数据有力地支持了BMP信号的基础和配体刺激失调，这与在这种情况下对突变ACVR1受体的计算机模拟研究一致。这项研究极大地扩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体中BMP信号失调的理解。
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