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.