Pathobiology of Paget's Disease of Bone.
Pathobiology of Paget's Disease of Bone.
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DOI：
10.11005/jbm.2014.21.2.85
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发表时间：
2014-05
影响因子：
--
通讯作者：
Roodman GD
中科院分区：
文献类型：
--
作者：
Galson DL;Roodman GD
骨的佩吉特病的特征在于高度局部区域的骨吸收增加，伴随着旺盛但异常的新骨形成，伴有破骨细胞中的原发性细胞异常。佩吉特病为理解破骨细胞形成和破骨细胞诱导的成骨细胞活性的分子机制提供了一个重要的范例。遗传和环境病因都与佩吉特病有关，但它们的相对作用才刚刚开始被确定。迄今为止，与佩吉特病相关的编码区中具有突变的唯一基因是编码p62蛋白的多价体-1（SQSTM 1），并且这些突变导致破骨细胞中NF-B的细胞因子活化升高，但不诱导“佩吉特破骨细胞”表型。此外，与佩吉特相关的基因突变似乎不足以引起佩吉特病，可能需要额外的易感基因座或环境因素。在提示诱发佩吉特病的环境因素中，对慢性麻疹（MV）感染的研究最多。麻疹病毒核衣壳基因（MVNP）在破骨细胞中的表达诱导小鼠产生pagetic样破骨细胞和骨病变。此外，在破骨细胞中同时表达MVNP和种系突变型p62的小鼠发生了与佩吉特病患者惊人相似的显著佩吉特骨病变。因此，环境和遗传因素之间的相互作用对佩吉特病的发展显得很重要。本文综述了突变型p62基因表达和MVNP对破骨细胞和成骨细胞活性的影响及其在佩吉特骨病发生发展中的作用机制。
Paget's disease of bone is characterized by highly localized areas of increased bone resorption accompanied by exuberant, but aberrant new bone formation with the primary cellular abnormality in osteoclasts. Paget's disease provides an important paradigm for understanding the molecular mechanisms regulating both osteoclast formation and osteoclast-induced osteoblast activity. Both genetic and environmental etiologies have been implicated in Paget's disease, but their relative contributions are just beginning to be defined. To date, the only gene with mutations in the coding region linked to Paget's disease is sequestosome-1 (SQSTM1), which encodes the p62 protein, and these mutations lead to elevated cytokine activation of NF-B in osteoclasts but do not induce a "pagetic osteoclast" phenotype. Further, genetic mutations linked to Paget's appear insufficient to cause Paget's disease and additional susceptibility loci or environmental factors may be required. Among the environmental factors suggested to induce Paget's disease, chronic measles (MV) infection has been the most studied. Expression of the measles virus nucleocapsid gene (MVNP) in osteoclasts induces pagetic-like osteoclasts and bone lesions in mice. Further, mice expressing both MVNP in osteoclasts and germline mutant p62 develop dramatic pagetic bone lesions that were strikingly similar to those seen in patients with Paget's disease. Thus, interactions between environmental and genetic factors appear important to the development of Paget's disease. In this article we review the mechanisms responsible for the effects of mutant p62 gene expression and MVNP on osteoclast and osteoblast activity, and how they may contribute to the development of Paget's disease of bone.