Fibrodysplasia ossificans progressiva (FOP) is a rare disabling disease 
characterized by heterotopic ossification for which there is currently no 
treatment available. FOP has been linked recently to a heterozygous R206H 
mutation in the bone morphogenetic protein (BMP) type I receptor activin 
receptor-like kinase 2 (ALK2). Expression of the mutant ALK2-R206H receptor 
(FOP-ALK2) results in increased phosphorylation of the downstream Smad1 effector 
proteins and elevated basal BMP-dependent transcriptional reporter activity, 
indicating that FOP-ALK2 is constitutively active. FOP-ALK2-induced 
transcriptional activity could be blocked by overexpressing either of the 
inhibitory Smads, Smad6 or -7, or by treatment with the pharmacological BMP type 
I receptor inhibitor dorsomorphin. However, in contrast to wild-type ALK2, 
FOP-ALK2 is not inhibited by the negative regulator FKBP12. Mesenchymal cells 
expressing the FOP-ALK2 receptor are more sensitive to undergoing BMP-induced 
osteoblast differentiation and mineralization. In vivo bone formation was 
assessed by loading human mesenchymal stem cells (hMSCs) expressing the 
ALK2-R206H receptor onto calcium phosphate scaffolds and implantation in nude 
mice. Compared with control cells FOP-ALK2-expressing cells induced increased 
bone formation. Taken together, the R206H mutation in ALK2 confers constitutive 
activity to the mutant receptor, sensitizes mesenchymal cells to BMP-induced 
osteoblast differentiation, and stimulates new bone formation. We have generated 
an animal model that can be used as a stepping stone for preclinical studies 
aimed at inhibiting the heterotopic ossification characteristic of FOP.