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ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP‐induced osteoblast differentiation and bone formation
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 recepto...
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Published in: | Journal of bone and mineral research 2010-06, Vol.25 (6), p.1208-1215 |
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Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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. © 2010 American Society for Bone and Mineral Research |
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ISSN: | 0884-0431 1523-4681 |
DOI: | 10.1359/jbmr.091110 |