dorsomorphin and Myositis-Ossificans

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by progressive heterotopic bone formation in skeletal muscle tissue. In patients with FOP, heterozygous mutations have been identified in the BMP type I receptor, ALK2. This finding stimulates establishment of some animal models of FOP and development of novel treatments for FOP.

Topics: Activin Receptors, Type I; Animals; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Proteins; Disease Models, Animal; Drug Design; Genes, Dominant; Humans; Muscles; Mutation; Myositis Ossificans; Pyrazoles; Pyrimidines; Regeneration; Signal Transduction

Drug discovery and development is commonly schematized as a "pipeline," and, although appreciated by drug developers to be a useful oversimplification, this cartology may perpetuate inaccurate notions of straightforwardness and is of minimal utility for process engineering to improve efficiency. To create a more granular schema, a group of drug developers, researchers, patient advocates, and regulators developed a crowdsourced atlas of the steps involved in translating basic discoveries into health interventions, annotated with the steps that are particularly prone to difficulty or failure. This Drug Discovery, Development, and Deployment Map (4DM), provides a network view of the process, which will be useful for communication and education to those new to the field, orientation and navigation of individual projects, and prioritization of technology development and re-engineering endeavors to improve efficiency and effectiveness. The 4DM is freely available for utilization, modification, and further development by stakeholders across the translational ecosystem.

Topics: Biomedical Technology; Clinical Trials as Topic; Communication; Drug Development; Drug Discovery; Humans; Intersectoral Collaboration; Learning; Myositis Ossificans; National Academies of Science, Engineering, and Medicine, U.S., Health and Medicine Division; Neuropeptide Y; Obesity; Polycystic Kidney, Autosomal Dominant; Pyrazoles; Pyrimidines; Research Design; Translational Research, Biomedical; United States; United States Food and Drug Administration

Bone morphogenetic protein (BMP) receptor kinases are tightly regulated to control development and tissue homeostasis. Mutant receptor kinase domains escape regulation leading to severely degenerative diseases and represent an important therapeutic target. Fibrodysplasia ossificans progressiva (FOP) is a rare but devastating disorder of extraskeletal bone formation. FOP-associated mutations in the BMP receptor ALK2 reduce binding of the inhibitor FKBP12 and promote leaky signaling in the absence of ligand. To establish structural mechanisms of receptor regulation and to address the effects of FOP mutation, we determined the crystal structure of the cytoplasmic domain of ALK2 in complex with the inhibitors FKBP12 and dorsomorphin. FOP mutations break critical interactions that stabilize the inactive state of the kinase, thereby facilitating structural rearrangements that diminish FKBP12 binding and promote the correct positioning of the glycine-serine-rich loop and αC helix for kinase activation. The balance of these effects accounts for the comparable activity of R206H and L196P. Kinase activation in the clinically benign mutant L196P is far weaker than R206H but yields equivalent signals due to the stronger interaction of FKBP12 with R206H. The presented ALK2 structure offers a valuable template for the further design of specific inhibitors of BMP signaling.

Topics: Activin Receptors, Type I; Amino Acid Motifs; Animals; Bone Morphogenetic Protein 4; Catalytic Domain; Crystallography, X-Ray; Enzyme Activation; Gene Expression Regulation; Genes, Reporter; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Luciferases, Firefly; Mice; Models, Molecular; Mutation, Missense; Myositis Ossificans; Protein Binding; Pyrazoles; Pyrimidines; Signal Transduction; Tacrolimus; Tacrolimus Binding Protein 1A

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by congenital malformation of the great toes and by progressive heterotopic bone formation in muscle tissue. Recently, a mutation involving a single amino acid substitution in a bone morphogenetic protein (BMP) type I receptor, ALK2, was identified in patients with FOP. We report here that the identical mutation, R206H, was observed in 19 Japanese patients with sporadic FOP. This mutant receptor, ALK2(R206H), activates BMP signaling without ligand binding. Moreover, expression of Smad1 and Smad5 was up-regulated in response to muscular injury. ALK2(R206H) with Smad1 or Smad5 induced osteoblastic differentiation that could be inhibited by Smad7 or dorsomorphin. Taken together, these findings suggest that the heterotopic bone formation in FOP may be induced by a constitutively activated BMP receptor signaling through Smad1 or Smad5. Gene transfer of Smad7 or inhibition of type I receptors with dorsomorphin may represent strategies for blocking the activity induced by ALK2(R206H) in FOP.

Topics: Activin Receptors, Type I; Amino Acid Substitution; Animals; Bone Morphogenetic Protein Receptors, Type I; Cell Differentiation; Cell Line; Female; Humans; Male; Matrix Metalloproteinases, Secreted; Mice; Mutation, Missense; Myositis Ossificans; Osteoblasts; Osteogenesis; Pyrazoles; Pyrimidines; Signal Transduction; Smad1 Protein; Smad5 Protein; Smad7 Protein

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disorder characterized by progressive heterotopic bone formation in muscle tissues. A common mutation among FOP patients has been identified in ALK2, ALK2(R206H), which encodes a constitutively active bone morphogenetic protein (BMP) receptor. Recently, a unique mutation of ALK2, ALK2(G356D), was identified to be a novel mutation in a Japanese FOP patient who had unique clinical features. Over-expression of ALK2(G356D) induced phosphorylation of Smad1/5/8 and activated Id1-luc and alkaline phosphatase activity in myoblasts. However, the over-expression failed to activate phosphorylation of p38, ERK1/2, and CAGA-luc activity. These ALK2(G356D) activities were weaker than those of ALK2(R206H), and they were suppressed by a specific inhibitor of the BMP-regulated Smad pathway. These findings suggest that ALK2(G356D) induces heterotopic bone formation via activation of a BMP-regulated Smad pathway. The quantitative difference between ALK2(G356D) and ALK2(R206H) activities may have caused the phenotypic differences in these patients.

Topics: Activin Receptors, Type I; Amino Acid Substitution; Animals; Aspartic Acid; Bone Morphogenetic Protein Receptors, Type I; Cell Differentiation; Glycine; Humans; Ligands; Mice; Muscle Development; Mutation; Myoblasts; Myositis Ossificans; Osteoblasts; Pyrazoles; Pyrimidines; Signal Transduction; Smad Proteins

Fibrodysplasia ossificans progressiva (FOP) is a congenital disorder of progressive and widespread postnatal ossification of soft tissues and is without known effective treatments. Affected individuals harbor conserved mutations in the ACVR1 gene that are thought to cause constitutive activation of the bone morphogenetic protein (BMP) type I receptor, activin receptor-like kinase-2 (ALK2). Here we show that intramuscular expression in the mouse of an inducible transgene encoding constitutively active ALK2 (caALK2), resulting from a glutamine to aspartic acid change at amino acid position 207, leads to ectopic endochondral bone formation, joint fusion and functional impairment, thus phenocopying key aspects of human FOP. A selective inhibitor of BMP type I receptor kinases, LDN-193189 (ref. 6), inhibits activation of the BMP signaling effectors SMAD1, SMAD5 and SMAD8 in tissues expressing caALK2 induced by adenovirus specifying Cre (Ad.Cre). This treatment resulted in a reduction in ectopic ossification and functional impairment. In contrast to localized induction of caALK2 by Ad.Cre (which entails inflammation), global postnatal expression of caALK2 (induced without the use of Ad.Cre and thus without inflammation) does not lead to ectopic ossification. However, if in this context an inflammatory stimulus was provided with a control adenovirus, ectopic bone formation was induced. Like LDN-193189, corticosteroid inhibits ossification in Ad.Cre-injected mutant mice, suggesting caALK2 expression and an inflammatory milieu are both required for the development of ectopic ossification in this model. These results support the role of dysregulated ALK2 kinase activity in the pathogenesis of FOP and suggest that small molecule inhibition of BMP type I receptor activity may be useful in treating FOP and heterotopic ossification syndromes associated with excessive BMP signaling.

Topics: Animals; Bone Morphogenetic Protein Receptors, Type I; Cell Line; Disease Models, Animal; Mice; Mice, Inbred C57BL; Molecular Structure; Myositis Ossificans; Ossification, Heterotopic; Pyrazoles; Pyrimidines; Signal Transduction; Tomography, X-Ray Computed