title: Bone morphogenetic protein-4 regulation in fibrodysplasia ossificans progressiva.
abstract: Fibrodysplasia ossificans progressiva is a rare genetic disorder in which connective tissues are replaced with heterotopic bone through an endochondral process. Bone morphogenetic protein-4 messenger ribonucleic acid and protein levels are elevated in the cells of patients with fibrodysplasia ossificans progressiva, but the molecular mechanism of this steady-state elevation is unknown. Nuclear run-on assays and messenger ribonucleic acid stability assays were done to examine the molecular mechanisms of increased bone morphogenetic protein-4 messenger ribonucleic acid. The bone morphogenetic protein-4 transcription rate in patient cells was found to be enhanced fivefold to sevenfold over normal control cells, suggesting that elevated steady-state levels of this transcript were attributable at least in part to an enhancement in transcription initiation. The stability of bone morphogenetic protein-4 messenger ribonucleic acid was found to be similar for patient and control cells and to have an extremely brief half-life, with bone morphogenetic protein-4 messenger ribonucleic acid almost completely decayed (75%) by 40 minutes. This unusually brief half-life suggests that a high fidelity control over temporal expression of the bone morphogenetic protein 4-message can be maintained. The data document that enhanced transcription rather than increased messenger ribonucleic acid stability is responsible for the elevation in steady-state levels of bone morphogenetic protein-4 messenger ribonucleic acid, and suggest that an inappropriate enhancement of the rate of bone morphogenetic protein-4 transcription plays a critical role in the molecular pathophysiology of fibrodysplasia ossificans progressiva.
authors.affiliation: Department of Orthopaedic Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6081, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Olmsted
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Kaplan
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Shore
mesh_terms: D000328:Adult; D015152:Blotting, Northern; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D002648:Child; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D009221:Myositis Ossificans / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins