FOP is a disorder in which skeletal muscle is progressively replaced with bone. 
FOP lymphocytes, a model system for exploring the BMP pathway in these patients, 
exhibit a defect in BMPRIA internalization and increased activation of 
downstream signaling, suggesting that altered BMP receptor trafficking underlies 
ectopic bone formation in this disease.
INTRODUCTION: Fibrodysplasia ossificans progressiva (FOP) is a severely 
disabling disorder characterized by progressive heterotopic ossification of 
connective tissues. Whereas the genetic defect and pathophysiology of this 
condition remain enigmatic, BMP4 mRNA and protein are overexpressed, and mRNAs 
for a subset of secreted BMP antagonists are not synthesized at appropriate 
levels in cultured lymphocytes from FOP patients. These data suggest involvement 
of altered BMP signaling in the disease. In this study, we investigate whether 
the abnormality is associated with defective BMP receptor function in 
lymphocytes.
MATERIALS AND METHODS: Cell surface proteins were quantified by 
fluorescence-activated cell sorting (FACS). Protein phosphorylation was assayed 
by immunoprecipitation and immunoblotting. Protein synthesis and degradation 
were examined by [35S]methionine labeling and pulse-chase assays. mRNA was 
detected by RT-PCR.
RESULTS: FOP lymphocytes expressed 6-fold higher levels of BMP receptor type IA 
(BMPRIA) on the cell surface compared with control cells and displayed a marked 
reduction in ligand-stimulated internalization and degradation of BMPRIA. 
Moreover, in control cells, BMP4 treatment increased BMPRIA phosphorylation, 
whereas BMPRIA showed ligand-insensitive constitutive phosphorylation in FOP 
cells. Our data additionally support that the p38 mitogen-activated protein 
kinase (MAPK) signaling pathway is a major BMP signaling pathway in these cell 
lines and that expression of inhibitor of DNA binding and differentiation 1 
(ID-1), a transcriptional target of BMP signaling, is enhanced in FOP cells.
CONCLUSIONS: These data extend our previous observations of misregulated BMP4 
signaling in FOP lymphocytes and show that cell surface overabundance and 
constitutive phosphorylation of BMPRIA are associated with a defect in receptor 
internalization. Altered BMP receptor trafficking may play a significant role in 
FOP pathogenesis.