Age-Dependent Demise of GNAS-Mutated Skeletal Stem Cells and "Normalization" of Fibrous Dysplasia of Bone
Age-Dependent Demise of GNAS-Mutated Skeletal Stem Cells and "Normalization" of Fibrous Dysplasia of Bone
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DOI：
10.1359/jbmr.080609
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发表时间：
2008-11-01
影响因子：
6.2
通讯作者：
Bianco, Paolo
中科院分区：
文献类型：
--
作者：
Kuznetsov, Sergei A.;Cherman, Natasha;Bianco, Paolo
我们通过评估FD病变中突变集落形成单位成纤维细胞（CFU-Fs）的频率，研究了骨骼（“间充质”）干细胞背景下体细胞嵌合在骨纤维异常增殖症（FD）中的作用。在某些情况下，从未受影响的部位，在一系列的病人。突变CFU-F的百分比与年龄之间存在紧密的负相关性，这表明在年轻患者的样本中观察到的旺盛的细胞凋亡引起的突变干细胞的死亡。老年患者。观察到部分或完全正常的骨/骨髓组织学。关于体内移植。FD听小骨仅由鉴定出突变CFU-F的细胞株产生。缺乏突变CFU-F（但突变阳性）的菌株不能再生FD小骨。这些数据表明，GNAS突变仅在克隆性骨骼干细胞中具有致病性。从这些数据中，我们已经发展了新的概念“正常化”的FD。随着病变的老化，突变的干细胞不能自我更新，它们的后代被凋亡所消耗。而剩余的正常干细胞存活并自我更新。并且能够形成正常结构。这表明激活GNAS突变破坏了骨骼干细胞自我更新所需的途径。
We Studied the role of somatic mosaicism in fibrous dysplasia of bone (FD) within the context of skeletal ("mesenchymal") stern cells by assessing the frequency of mutated colony forming unit-fibroblasts (CFU-Fs) from FD lesions. and in some cases, from unaffected sites, in a series of patients. There was a tight inverse correlation between the percentage mutant CFU-F versus age, suggesting demise of mutant stem cells caused by exuberant apoptosis noted in samples from young patients. In older patients. either partially or completely normal bone/marrow histology was observed. On in vivo transplantation. FD ossicles were generated only by cell strains in which mutant CFU-Fs were identified. strains that lacked mutant CFU-F (but were mutation positive) failed to regenerate an FD ossicle. These data indicate that GNAS Mutations are only Pathogenic when in clonogenic skeletal stern cells. From these data, we have evolved the novel concept of "normalization" of FD. As a lesion ages, mutant stern cells fail to self-renew, and their progeny are consumed by apoptosis. whereas residual normal stern cells survive, self-renew. and enable formation of a normal Structure. This suggests that activating GNAS Mutations disrupt a pathway that is required for skeletal stern cell self-renewal.