TY - JOUR
T1 - BMP type I receptor inhibition reduces heterotopic ossification
AU - Yu, Paul B.
AU - Deng, Donna Y.
AU - Lai, Carol S.
AU - Hong, Charles C.
AU - Cuny, Gregory D.
AU - Bouxsein, Mary L.
AU - Hong, Deborah W.
AU - McManus, Patrick M.
AU - Katagiri, Takenobu
AU - Sachidanandan, Chetana
AU - Kamiya, Nobuhiro
AU - Fukuda, Tomokazu
AU - Mishina, Yuji
AU - Peterson, Randall T.
AU - Bloch, Kenneth D.
N1 - Funding Information:
We thank P. ten Dijke (Leiden University Medical Center) for providing BRE-Luc and CAGA-Luc and K. Miyazono (University of Tokyo) for providing caALK2, caALK3, caALK4, caALK5, caALK6 and caALK7. We are grateful to H. Beppu, E. Schipani, H. Kronenberg, A. Wagers, J. Groppe, W. Zapol and F. Kaplan for insightful discussions and technical expertise, A. Graveline and D. Panus for technical assistance and E. Buys for technical expertise. This work was supported by US National Institutes of Health grants HL079943 (P.B.Y.) and HL074352 (K.D.B.), the US National Institute of Environmental Health Sciences Intramural Research Program grant ES071003-10 (Y.M.) and Partners Healthcare. This work was also supported by a Howard Hughes Medical Institute Early Career Award (P.B.Y.), a Pulmonary Hypertension Association Mentored Clinical Scientist Award (P.B.Y.), a grant from the GlaxoSmithKline Research & Education Foundation for Cardiovascular Disease (P.B.Y.) and a Developmental Grant from the Center for Research in Fibrodysplasia Ossificans Progressiva and Related Disorders at the University of Pennsylvania (C.C.H.).
PY - 2008/12
Y1 - 2008/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=57349171954&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=57349171954&partnerID=8YFLogxK
U2 - 10.1038/nm.1888
DO - 10.1038/nm.1888
M3 - Article
C2 - 19029982
AN - SCOPUS:57349171954
SN - 1078-8956
VL - 14
SP - 1363
EP - 1369
JO - Nature Medicine
JF - Nature Medicine
IS - 12
ER -