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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.
J Bone Miner Res. 2010 Jun; 25(6):1208-15.JB

Abstract

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.

Authors+Show Affiliations

Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19929436

Citation

van Dinther, Maarten, et al. "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." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 25, no. 6, 2010, pp. 1208-15.
van Dinther M, Visser N, de Gorter DJ, et al. 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. J Bone Miner Res. 2010;25(6):1208-15.
van Dinther, M., Visser, N., de Gorter, D. J., Doorn, J., Goumans, M. J., de Boer, J., & ten Dijke, P. (2010). 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. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 25(6), 1208-15. https://doi.org/10.1359/jbmr.091110
van Dinther M, et al. 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. J Bone Miner Res. 2010;25(6):1208-15. PubMed PMID: 19929436.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - van Dinther,Maarten, AU - Visser,Nils, AU - de Gorter,David J J, AU - Doorn,Joyce, AU - Goumans,Marie-José, AU - de Boer,Jan, AU - ten Dijke,Peter, PY - 2009/11/26/entrez PY - 2009/11/26/pubmed PY - 2010/9/2/medline SP - 1208 EP - 15 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J Bone Miner Res VL - 25 IS - 6 N2 - 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. SN - 1523-4681 UR - https://www.unboundmedicine.com/medline/citation/19929436/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_ L2 - https://doi.org/10.1359/jbmr.091110 DB - PRIME DP - Unbound Medicine ER -