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 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.
van Dinther
Maarten
M
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
Visser
Nils
N
de Gorter
David J J
DJ
Doorn
Joyce
J
Goumans
Marie-José
MJ
de Boer
Jan
J
ten Dijke
Peter
P
D030201:Activin Receptors, Type I / Q000235:genetics* / Q000378:metabolism; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002130:Calcium Phosphates / Q000494:pharmacology; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002828:Choristoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009221:Myositis Ossificans / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D054457:Tissue Scaffolds
D019485:Bone Morphogenetic Proteins; D002130:Calcium Phosphates; D050505:Mutant Proteins; C020243:calcium phosphate; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; D052005:Bone Morphogenetic Protein Receptors, Type I