Letter abstract
Nature Medicine 14, 1363 - 1369 (2008)
Published online: 30 November 2008 | Corrected online: 4 December 2008 | doi:10.1038/nm.1888
There is an Erratum (January 2009) associated with this Letter.
BMP type I receptor inhibition reduces heterotopic ossification
Paul B Yu1,2, Donna Y Deng1, Carol S Lai1, Charles C Hong3, Gregory D Cuny4, Mary L Bouxsein5, Deborah W Hong1, Patrick M McManus1, Takenobu Katagiri6, Chetana Sachidanandan1, Nobuhiro Kamiya7, Tomokazu Fukuda7, Yuji Mishina7,8,9, Randall T Peterson1,9 & Kenneth D Bloch1,2
Fibrodysplasia ossificans progressiva (FOP) is a congenital disorder of progressive and widespread postnatal ossification of soft tissues1, 2, 3, 4 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)5. 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.
- Division of Cardiology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Thier 505, 50 Blossom Street, Boston, Massachusetts 02114, USA
- Anesthesia Centre for Critical Care Research, Massachusetts General Hospital and Harvard Medical School, Thier 505, 50 Blossom Street, Boston, Massachusetts 02114, USA.
- Division of Cardiovascular Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, Tennessee 37232, USA.
- Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA.
- Orthopedic Biomechanics Laboratory, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
- Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
- Molecular Developmental Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Road, Research Triangle Park, North Carolina 27709, USA.
- Present address: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, 4222A Dental, 1011 North University Avenue, Ann Arbor, Michigan 48109, USA.
- These authors contributed equally to this work.
Correspondence to: e-mail: pbyu@partners.org
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
Ligand-dependent ubiquitination of Smad3 is regulated by casein kinase 1 gamma 2, an inhibitor of TGF-β signalingOncogene Original Article
Mutational analysis of the ACVR1 gene in Italian patients affected with fibrodysplasia ossificans progressiva: confirmations and advancementsEuropean Journal of Human Genetics Article Response
A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressivaNature Genetics Brief Communication (01 May 2006)
Amino-bisphosphonates in heterotopic ossification: first experience in five consecutive casesSpinal Cord Original Article
See all 7 matches for Research
