Constitutive expression of Gsα(R201C) in mice produces a heritable, direct replica of human fibrous dysplasia bone pathology and demonstrates its natural history.
Constitutive expression of Gsα(R201C) in mice produces a heritable, direct replica of human fibrous dysplasia bone pathology and demonstrates its natural history.
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DOI：
10.1002/jbmr.2267
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发表时间：
2014-11
影响因子：
6.2
通讯作者：
Riminucci, Mara
中科院分区：
文献类型：
--
作者：
Saggio, Isabella;Remoli, Cristina;Spica, Emanuela;Cersosimo, Stefania;Sacchetti, Benedetto;Robey, Pamela G.;Holmbeck, Kenn;Cumano, Ana;Boyde, Alan;Bianco, Paolo;Riminucci, Mara
骨纤维发育不良（FD）是一种致残性骨骼疾病，与编码刺激性G蛋白（Gs）α亚基的基因的合子后突变（R201 C，R201 H）相关。通过引起骨和骨髓的特征性结构破坏，该疾病导致受影响骨的畸形、矿化不足和骨折，在儿童或青少年中出现严重的发病率。这种疾病在人类中缺乏遗传性被认为反映了生殖系传播的激活Gsα突变的胚胎致死性，这些突变只能通过体细胞嵌合体存活。我们已经产生了多个组成型表达Gsα R201 C的小鼠品系，并形成了人类FD的遗传性、组织病理学精确复制品。新生儿和胚胎组织以及胚胎干细胞中的转基因表达与骨骼组织的正常发育和骨骼细胞的分化相关。与人类一样，小鼠的FD病变仅在出生后发生;明确的空间和时间模式表征了骨骼病变的发作和进展。在个体骨中，病变通过三个不同的组织病理学阶段发展：主要建模阶段，定义为骨内膜/骨髓过量骨形成和正常吸收;第二阶段，过度、不适当的重塑;和第三纤维发育不良阶段，在≥1岁的小鼠中再现了人骨病理学的完整复制品。Gsα突变足以引起FD，并且本身与小鼠的生殖系传播和正常胚胎发育相容。我们的新型鼠系构成了FD的第一个模型。
Fibrous dysplasia of bone (FD) is a crippling skeletal disease associated with post zygotic mutations (R201C, R201H) of the gene encoding the α subunit of the stimulatory G protein, Gs. By causing a characteristic structural subversion of bone and bone marrow, the disease results in deformity, hypomineralization, and fracture of the affected bones, with severe morbidity arising in childhood or adolescence. Lack of inheritance of the disease in humans is thought to reflect embryonic lethality of germline-transmitted activating Gsα mutations, which would only survive through somatic mosaicism. We have generated multiple lines of mice that express GsαR201C constitutively and develop an inherited, histopathologically exact replica of human FD. Robust transgene expression in neonatal and embryonic tissues, and embryonic stem (ES) cells was associated with normal development of skeletal tissues and differentiation of skeletal cells. As in humans, FD lesions in mice developed only in the postnatal life; a defined spatial and temporal pattern characterized the onset and progression of lesions across the skeleton. In individual bones, lesions developed through a sequence of three distinct histopathological stages: a primary modeling phase defined by endosteal/medullary excess bone formation, and normal resorption; a secondary phase, with excess, inappropriate remodeling; and a tertiary fibrous dysplastic phase, which reproduced a full-blown replica of the human bone pathology in mice of age ≥1 year. Gsα mutations are sufficient to cause FD, and are per se compatible with germline transmission and normal embryonic development in mice. Our novel murine lines constitute the first model of FD.
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影响因子：
5.8
作者：
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通讯作者：
Spada, A
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CONTI, M