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BMP type I receptor inhibition reduces heterotopic [corrected] ossification.
- Source :
-
Nature medicine [Nat Med] 2008 Dec; Vol. 14 (12), pp. 1363-9. Date of Electronic Publication: 2008 Nov 30. - Publication Year :
- 2008
-
Abstract
- 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.
- Subjects :
- Animals
Bone Morphogenetic Protein Receptors, Type I metabolism
Cell Line
Disease Models, Animal
Mice
Mice, Inbred C57BL
Molecular Structure
Myositis Ossificans genetics
Myositis Ossificans metabolism
Myositis Ossificans pathology
Ossification, Heterotopic genetics
Ossification, Heterotopic pathology
Pyrazoles chemistry
Pyrazoles therapeutic use
Pyrimidines chemistry
Pyrimidines therapeutic use
Signal Transduction drug effects
Tomography, X-Ray Computed
Bone Morphogenetic Protein Receptors, Type I antagonists & inhibitors
Ossification, Heterotopic drug therapy
Ossification, Heterotopic metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1546-170X
- Volume :
- 14
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Nature medicine
- Publication Type :
- Academic Journal
- Accession number :
- 19029982
- Full Text :
- https://doi.org/10.1038/nm.1888