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.

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: Maarten van Dinther, Nils Visser, David J J de Gorter, Joyce Doorn, Marie-José Goumans, Jan de Boer, Peter ten Dijke
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 25 Issue 6 Pg. 1208-15 (Jun 2010) ISSN: 1523-4681 [Electronic] United States
• PMID: 19929436 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2010 American Society for Bone and Mineral Research.

Chemical References

• Bone Morphogenetic Proteins
• Calcium Phosphates
• Mutant Proteins
• calcium phosphate
• ACVR1 protein, human
• Activin Receptors, Type I
• Bone Morphogenetic Protein Receptors, Type I

Topics

• Activin Receptors, Type I (genetics, metabolism)
• Amino Acid Substitution (genetics)
• Animals
• Bone Morphogenetic Protein Receptors, Type I (genetics, metabolism)
• Bone Morphogenetic Proteins (pharmacology)
• Calcium Phosphates (pharmacology)
• Cattle
• Cell Differentiation (drug effects)
• Cell Line
• Cell Proliferation (drug effects)
• Choristoma (metabolism, pathology)
• Humans
• Mesenchymal Stem Cells (cytology, drug effects, enzymology)
• Mice
• Mutant Proteins (metabolism)
• Mutation (genetics)
• Myositis Ossificans (enzymology, genetics, pathology)
• Osteoblasts (cytology, drug effects)
• Osteogenesis (drug effects)
• Tissue Scaffolds