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Dysregulated BMP signaling and enhanced osteogenic differentiation of connective tissue progenitor cells from patients with fibrodysplasia ossificans progressiva (FOP).
J Bone Miner Res. 2008 Mar; 23(3):305-13.JB

Abstract

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.

Authors+Show Affiliations

The Center for Research in FOP and Related Disorders, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17967130

Citation

Billings, Paul C., et al. "Dysregulated BMP Signaling and Enhanced Osteogenic Differentiation of Connective Tissue Progenitor Cells From Patients With Fibrodysplasia Ossificans Progressiva (FOP)." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 23, no. 3, 2008, pp. 305-13.
Billings PC, Fiori JL, Bentwood JL, et al. Dysregulated BMP signaling and enhanced osteogenic differentiation of connective tissue progenitor cells from patients with fibrodysplasia ossificans progressiva (FOP). J Bone Miner Res. 2008;23(3):305-13.
Billings, P. C., Fiori, J. L., Bentwood, J. L., O'Connell, M. P., Jiao, X., Nussbaum, B., Caron, R. J., Shore, E. M., & Kaplan, F. S. (2008). Dysregulated BMP signaling and enhanced osteogenic differentiation of connective tissue progenitor cells from patients with fibrodysplasia ossificans progressiva (FOP). Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 23(3), 305-13.
Billings PC, et al. Dysregulated BMP Signaling and Enhanced Osteogenic Differentiation of Connective Tissue Progenitor Cells From Patients With Fibrodysplasia Ossificans Progressiva (FOP). J Bone Miner Res. 2008;23(3):305-13. PubMed PMID: 17967130.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dysregulated BMP signaling and enhanced osteogenic differentiation of connective tissue progenitor cells from patients with fibrodysplasia ossificans progressiva (FOP). AU - Billings,Paul C, AU - Fiori,Jennifer L, AU - Bentwood,Jennifer L, AU - O'Connell,Michael P, AU - Jiao,Xiangyang, AU - Nussbaum,Burton, AU - Caron,Robert J, AU - Shore,Eileen M, AU - Kaplan,Frederick S, PY - 2007/10/31/pubmed PY - 2008/6/25/medline PY - 2007/10/31/entrez SP - 305 EP - 13 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J. Bone Miner. Res. VL - 23 IS - 3 N2 - UNLABELLED: 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. SN - 1523-4681 UR - https://www.unboundmedicine.com/medline/citation/17967130/Dysregulated_BMP_signaling_and_enhanced_osteogenic_differentiation_of_connective_tissue_progenitor_cells_from_patients_with_fibrodysplasia_ossificans_progressiva__FOP__ L2 - https://doi.org/10.1359/jbmr.071030 DB - PRIME DP - Unbound Medicine ER -