These authors contributed equally to this work
Dysregulated BMP Signaling and Enhanced Osteogenic Differentiation of Connective Tissue Progenitor Cells From Patients With Fibrodysplasia Ossificans Progressiva (FOP)†
Article first published online: 29 OCT 2007
Copyright © 2008 ASBMR
Journal of Bone and Mineral Research
Volume 23, Issue 3, pages 305–313, March 2008
How to Cite
Billings, P. C., Fiori, J. L., Bentwood, J. L., O'Connell, M. P., Jiao, X., Nussbaum, B., Caron, R. J., Shore, E. M. and Kaplan, F. S. (2008), Dysregulated BMP Signaling and Enhanced Osteogenic Differentiation of Connective Tissue Progenitor Cells From Patients With Fibrodysplasia Ossificans Progressiva (FOP). J Bone Miner Res, 23: 305–313. doi: 10.1359/jbmr.071030
The authors state that they have no conflicts of interest.
- Issue published online: 4 DEC 2009
- Article first published online: 29 OCT 2007
- Manuscript Accepted: 26 OCT 2007
- Manuscript Revised: 28 AUG 2007
- Manuscript Received: 14 JUN 2007
- fibrodysplasia ossificans progressiva;
- bone morphogenetic protein;
- bone morphogenetic protein signaling;
- activin receptor IA;
- connective tissue progenitor cells;
- SHED cells;
- heterotopic ossification
The study of FOP, a disabling genetic disorder of progressive heterotopic ossification, is hampered by the lack of readily available connective tissue progenitor cells. We isolated such cells from discarded primary teeth of patients with FOP and controls and discovered dysregulation of BMP signaling and rapid osteoblast differentiation in FOP cells compared with control cells.
Introduction: Fibrodysplasia ossificans progressiva (FOP), the most disabling condition of progressive heterotopic ossification in humans, is caused by a recurrent heterozygous missense mutation in activin receptor IA (ACVR1), a bone morphogenetic protein (BMP) type I receptor, in all classically affected individuals. A comprehensive understanding of FOP has been limited, in part, by a lack of readily available connective tissue progenitor cells in which to study the molecular pathology of this disorder.
Materials and Methods: We derived connective tissue progenitor cells from discarded primary teeth (SHED cells) of patients with FOP and controls and examined BMP signaling and osteogenic differentiation in these cells.
Results: SHED cells transmitted BMP signals through both the SMAD and p38 mitogen-activated protein kinase (MAPK) pathways and responded to BMP4 treatment by inducing BMP responsive genes. FOP cells showed ligand-independent BMP signaling and ligand-dependent hyper-responsiveness to BMP stimulation. Furthermore, FOP cells showed more rapid differentiation to an osteogenic phenotype than control cells.
Conclusions: This is the first study of BMP signaling and osteogenic differentiation in connective tissue progenitor cells from patients with FOP. Our data strongly support both basal and ligand-stimulated dysregulation of BMP signaling consistent with in silico studies of the mutant ACVR1 receptor in this condition. This study substantially extends our understanding of dysregulated BMP signaling in a progenitor cell population relevant to the pathogenesis of this catastrophic disorder of progressive ectopic ossification.