Expression of an active Gα(s) mutant in skeletal stem cells is sufficient and necessary for fibrous dysplasia initiation and maintenance.
Expression of an active Gα(s) mutant in skeletal stem cells is sufficient and necessary for fibrous dysplasia initiation and maintenance.
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骨骼干细胞中活性 G α(s) 突变体的表达对于纤维异常增殖的启动和维持是充分且必要的
DOI：
10.1073/pnas.1713710115
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发表时间：
2018-01-16
影响因子：
11.1
通讯作者：
Gutkind JS
中科院分区：
文献类型：
--
作者：
Zhao X;Deng P;Iglesias-Bartolome R;Amornphimoltham P;Steffen DJ;Jin Y;Molinolo AA;de Castro LF;Ovejero D;Yuan Q;Chen Q;Han X;Bai D;Taylor SS;Yang Y;Collins MT;Gutkind JS
我们通过在骨骼干细胞（ssc）中以一种时间控制和组织特异性的方式表达突变GNAS，建立了一种新的条件诱导小鼠纤维发育不良（FD）模型。典型的FD骨病变在突变胚胎和出生后小鼠中迅速发生。GNAS促进了PKA的激活和SSCs沿成骨谱系的增殖，但损害了它们向成熟成骨细胞的分化，并引发了破骨细胞生成和骨吸收的增加。停止GNAS表达后FD病变恢复。因此，GNAS突变对于FD的发生和维持是充分和必要的。该模型为确定FD进展的分子机制和加速开发更有效的治疗方案提供了宝贵的机会。纤维发育不良（FD）是由编码Gs刺激蛋白α-亚基的GNAS （R201C和R201H）的合子后激活突变引起的疾病。FD的特征是骨骼中出现异常纤维骨组织区域，导致骨骼畸形、骨折和疼痛。尽管明确定义了FD的遗传改变，但GNAS激活是否足以引发FD以及GNAS突变的分子和细胞后果在很大程度上仍未得到解决，目前尚无针对FD的靶向治疗方案。在这里，我们建立了一种条件四环素（Tet）诱导的动物模型，在骨骼干细胞（SSC）谱系中表达GαsR201C （Tet - GαsR201C/Prrx1-Cre/LSL-rtTA-IRES-GFP小鼠），在给予多西环素（Dox）不到2周的时间内，胚胎和成年小鼠都发生了典型的FD骨病变。条件g - α sr201c的表达促进了PKA的激活和SSCs沿成骨谱系的增殖，但阻止了它们向成熟成骨细胞的分化。相反，正如临床所见，形成了与纤维组织混合的编织骨区。GαsR201C引起核因子κ b配体受体激活因子（receptor activator of nuclear factor kappa-B ligand, Rankl）的同时表达，导致显著的破骨细胞生成和骨吸收。Dox停药消融GαsR201C表达导致FD样病变消退，支持g αs靶向药物治疗FD的理论基础。该模型显示FD样病变可以快速形成并在Gαs突变体表达停止后恢复，为确定FD发生和进展的分子机制提供了机会，并加速了新的治疗方案的开发。
We generated a novel conditional inducible mouse model of fibrous dysplasia (FD) by expressing mutant GNAS in skeletal stem cells (SSCs) in a temporally controlled and tissue-specific fashion. Typical FD bone lesions developed rapidly in mutant embryos and postnatal mice. GNAS promoted PKA activation and proliferation of SSCs along the osteogenic lineage but impaired their differentiation to mature osteoblasts and triggered increased osteoclastogenesis and bone resorption. FD lesions reverted on cessation of GNAS expression. Thus, GNAS mutation is sufficient and necessary for FD initiation and maintenance. This model provides a valuable opportunity to identify the molecular mechanism underlying FD progression and accelerate the development of more effective treatment options. Fibrous dysplasia (FD) is a disease caused by postzygotic activating mutations of GNAS (R201C and R201H) that encode the α-subunit of the Gs stimulatory protein. FD is characterized by the development of areas of abnormal fibroosseous tissue in the bones, resulting in skeletal deformities, fractures, and pain. Despite the well-defined genetic alterations underlying FD, whether GNAS activation is sufficient for FD initiation and the molecular and cellular consequences of GNAS mutations remains largely unresolved, and there are no currently available targeted therapeutic options for FD. Here, we have developed a conditional tetracycline (Tet)-inducible animal model expressing the GαsR201C in the skeletal stem cell (SSC) lineage (Tet–GαsR201C/Prrx1-Cre/LSL-rtTA-IRES-GFP mice), which develops typical FD bone lesions in both embryos and adult mice in less than 2 weeks following doxycycline (Dox) administration. Conditional GαsR201C expression promoted PKA activation and proliferation of SSCs along the osteogenic lineage but halted their differentiation to mature osteoblasts. Rather, as is seen clinically, areas of woven bone admixed with fibrous tissue were formed. GαsR201C caused the concomitant expression of receptor activator of nuclear factor kappa-B ligand (Rankl) that led to marked osteoclastogenesis and bone resorption. GαsR201C expression ablation by Dox withdrawal resulted in FD-like lesion regression, supporting the rationale for Gαs-targeted drugs to attempt FD cure. This model, which develops FD-like lesions that can form rapidly and revert on cessation of mutant Gαs expression, provides an opportunity to identify the molecular mechanism underlying FD initiation and progression and accelerate the development of new treatment options.
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影响因子：
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通过联合使用CRE介导的重组和四环素诱导，在小鼠中有条件和可诱导的转基因表达。
影响因子：
14.9
作者：
Belteki, Gusztav;Haigh, Jody;Kabacs, Nikolett;Haigh, Katharina;Sison, Karen;Costantini, Frank;Whitsett, Jeff;Quaggin, Susan E;Nagy, Andras
通讯作者：
Nagy, Andras