Skeletal progenitors and the GNAS gene: fibrous dysplasia of bone read through stem cells.
Skeletal progenitors and the GNAS gene: fibrous dysplasia of bone read through stem cells.
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DOI：
10.1677/jme-10-0097
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发表时间：
2010-12
影响因子：
3.5
通讯作者：
Bianco P
中科院分区：
文献类型：
--
作者：
Riminucci M;Robey PG;Saggio I;Bianco P
引起骨纤维异常增殖症（FD）的GNAS基因的激活突变导致骨骼祖细胞性质的显著变化，并且正是这些变化介导了该基因对骨的病理作用。突变的骨骼干细胞失去分化成脂肪细胞的能力，并失去原位维持和异位转移造血微环境的能力，导致FD中骨髓组织学异常。它们过度表达破骨细胞生成的分子效应物，从而促进不适当的骨吸收，导致FD骨的脆性。它们以正常水平表达磷酸盐调节激素FGF-23，其在FD患者血清中的过量与FD病变内的成骨细胞的质量相关，导致骨软化和FD骨的畸形，并揭示骨是调节磷酸盐的肾处理的内分泌器官。等位基因选择和干细胞选择的机制发生在突变的骨骼干细胞中，并有助于FD的内在多样性和随时间的演变。GNAS突变的病因学作用的定义标志着几十年的描述性观察和细胞和分子机制的定义之间的分水岭，这些机制将解释并有望治愈这种疾病。将干细胞置于中心舞台已经允许在十年内取得实质性进展，并承诺在未来取得更多进展。
Activating mutations of the GNAS gene, which causes fibrous dysplasia of bone (FD), lead to remarkable changes in the properties of skeletal progenitors, and it is these changes that mediate the pathological effect of this gene on bone. Mutated skeletal stem cells lose the ability to differentiate into adipocytes, and to maintain in situ, and transfer heterotopically, the hematopoietic microenvironment, leading to abnormal bone marrow histology in FD. They over-express molecular effectors of osteoclastogenesis, thus promoting inappropriate bone resorption leading to fragility of FD bone. They express at normal levels the phosphate-regulating hormone FGF-23, whose excess in the serum of FD patients correlates with the mass of osteogenic cells within FD lesion, leading to osteomalacia and deformity of the FD bone, and revealing that bone is an endocrine organ regulating renal handling of phosphate. Mechanisms of allelic selection and stem cell selection occur in mutated skeletal stem cells and contribute to the inherent diversity and evolution over time in FD. The definition of the etiological role of GNAS mutations marks the watershed between many decades of descriptive observation and the definition of cellular and molecular mechanisms that would explain and hopefully allow for a cure for the disease. Placing stem cells at center stage has permitted substantial advances in one decade, and promises more for the one to come.