EMBRYONIC OVEREXPRESSION OF THE C-FOS PROTOONCOGENE - A MURINE STEM-CELL CHIMERA APPLICABLE TO THE STUDY OF FIBRODYSPLASIA OSSIFICANS PROGRESSIVA IN HUMANS

Murine embryonic overexpression of the c-fos protooncogene leads to ea rly postnatal heterotopic chondrogenesis and osteogenesis with phenoty pic features similar to those seen in children who have the disabling heritable disease fibrodysplasia ossificans progressiva. The overexpre ssion of Fos in embryonic stem cell chimeras leads to heterotopic endo chondral osteogenesis at least in part through a bone morphogenetic pr otein 4 mediated signal transduction pathway. In contrast, early fibro dysplasia ossificans progressiva lesions express abundant bone morphog enetic protein 4, without abundant expression of c-Fos, suggesting tha t the primary molecular defect in fibrodysplasia ossificans progressiv a may be independent of the sustained Fos effects on chondrogenesis an d osteogenesis. Comparisons of the clinical, molecular, and pathogenet ic features of the c-Fos embryonic stem cell chimeras with those of fi brodysplasia ossificans progressiva provide insight into the earliest events in the molecular pathogenesis of genetically induced heterotopi c chondrogenesis and osteogenesis. The relevance of the c-Fos embryoni c stem cell chimera to the study of the currently untreatable human di sease fibrodysplasia ossificans progressiva demonstrates the power of using embryonic stem cell technology for generating gain of function m utations in the study of human bone disease.