Olmsted E A, Gannon F H, Wang Z Q, Grigoriadis A E, Wagner E F, Zasloff M A, Shore E M, Kaplan F S
Department of Orthopaedic Surgery, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Clin Orthop Relat Res. 1998 Jan(346):81-94.
Murine embryonic overexpression of the c-fos protooncogene leads to early postnatal heterotopic chondrogenesis and osteogenesis with phenotypic features similar to those seen in children who have the disabling heritable disease fibrodysplasia ossificans progressiva. The overexpression of Fos in embryonic stem cell chimeras leads to heterotopic endochondral osteogenesis at least in part through a bone morphogenetic protein 4 mediated signal transduction pathway. In contrast, early fibrodysplasia ossificans progressiva lesions express abundant bone morphogenetic protein 4, without abundant expression of c-Fos, suggesting that the primary molecular defect in fibrodysplasia ossificans progressiva may be independent of the sustained Fos effects on chondrogenesis and osteogenesis. Comparisons of the clinical, molecular, and pathogenetic features of the c-Fos embryonic stem cell chimeras with those of fibrodysplasia ossificans progressiva provide insight into the earliest events in the molecular pathogenesis of genetically induced heterotopic chondrogenesis and osteogenesis. The relevance of the c-Fos embryonic stem cell chimera to the study of the currently untreatable human disease fibrodysplasia ossificans progressiva demonstrates the power of using embryonic stem cell technology for generating gain of function mutations in the study of human bone disease.
c-fos原癌基因在小鼠胚胎中的过表达会导致出生后早期异位软骨生成和成骨，其表型特征与患有致残性遗传性疾病进行性骨化性纤维发育不良的儿童相似。胚胎干细胞嵌合体中Fos的过表达至少部分通过骨形态发生蛋白4介导的信号转导途径导致异位软骨内成骨。相比之下，早期进行性骨化性纤维发育不良病变表达大量骨形态发生蛋白4，但c-Fos表达不丰富，这表明进行性骨化性纤维发育不良的主要分子缺陷可能独立于Fos对软骨生成和成骨的持续影响。将c-Fos胚胎干细胞嵌合体与进行性骨化性纤维发育不良的临床、分子和致病特征进行比较，有助于深入了解基因诱导的异位软骨生成和成骨分子发病机制中的最早事件。c-Fos胚胎干细胞嵌合体与目前无法治疗的人类疾病进行性骨化性纤维发育不良研究的相关性，证明了利用胚胎干细胞技术在人类骨病研究中产生功能获得性突变的能力。
