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Embryonic overexpression of the c-Fos protooncogene. A murine stem cell chimera applicable to the study of fibrodysplasia ossificans progressiva in humans.

Abstract
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.
AuthorsE A Olmsted, F H Gannon, Z Q Wang, A E Grigoriadis, E F Wagner, M A Zasloff, E M Shore, F S Kaplan
JournalClinical orthopaedics and related research (Clin Orthop Relat Res) Issue 346 Pg. 81-94 (Jan 1998) ISSN: 0009-921X [Print] United States
PMID9577414 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • BMP2 protein, human
  • BMP4 protein, human
  • Bmp2 protein, mouse
  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins
  • Proto-Oncogene Proteins c-fos
  • Transforming Growth Factor beta
Topics
  • Animals
  • Blotting, Northern
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins (metabolism)
  • Cell Line
  • Humans
  • Immunohistochemistry
  • Mice
  • Myositis Ossificans (metabolism, pathology)
  • Proto-Oncogene Proteins c-fos (genetics, physiology)
  • Transforming Growth Factor beta
  • Transplantation Chimera

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