Bone morphogenetic protein-4 regulation in fibrodysplasia ossificans progressiva.

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.