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BMP type I receptor inhibition reduces heterotopic ossification

An Erratum to this article was published on 01 January 2009

This article has been updated


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.

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Figure 1: Mouse model of FOP.
Figure 2: Effect of LDN-193189 on BMP signaling and function.
Figure 3: Impact of LDN-193189 on ectopic ossification in vivo.
Figure 4: Impact of pharmacologic inhibition of BMP signaling and inflammation in the mouse FOP model.

Change history

  • 04 December 2008

    In the version of this article initially published, the title included a misspelling—‘heterotropic’ should have been ‘heterotopic’. Additionally, the fourth and fifth sentences of the abstract were incorrectly worded and have been corrected to state more clearly the role of Ad.Cre. These changes do not affect the scientific content of the text. The errors have been corrected in the HTML and PDF versions of the article.


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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.).

Author information

Authors and Affiliations



P.B.Y. wrote the manuscript. P.B.Y., D.Y.D. and C.S.L. designed and performed experiments and analyzed data. G.D.C., P.B.Y., K.D.B. and R.T.P. helped to design, synthesize and evaluate dorsomorphin derivatives, and G.D.C. provided pharmacokinetic data. M.L.B. provided technical expertise and μCT tomography data. D.W.H. and P.M.M. performed experiments. C.S. tested the efficacy of the dorsomorphin derivative with additional assays. N.K. performed control experiments. Y.M. and T.F. provided key experimental reagents. T.K. provided reagents and experimental advice. C.C.H., Y.M. and K.D.B. provided feedback and experimental advice, and P.B.Y. and K.D.B. edited the manuscript.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–7 (PDF 603 kb)

Supplementary Video 1

A wild-type mouse injected with Ad.Cre in the left hindlimb (P7), shown at P60. No deficits in limb function or gait are apparent. (MOV 1633 kb)

Supplementary Video 2

A conditional caALK2 mouse injected with Ad.Cre in the left hindlimb (P7), shown at P60. Severe fixed extension of the left hindlimb prevents use of the limb during ambulation. (MOV 3987 kb)

Supplementary Video 3

Vehicle-treated, Ad.Cre-injected conditional caALK2 mouse shown at P15. Mild impairment of gait due to decreased range-of-motion of the knee and hip joints. (MOV 2955 kb)

Supplementary Video 4

Vehicle-treated, Ad.Cre-injected conditional caALK2 mouse shown at P30. Severe gait impairment due to fixed extension of knee, hip and ankle joints. (MOV 1338 kb)

Supplementary Video 5

LDN-193189-treated, Ad.Cre-injected conditional caALK2 mouse shown at P15. No impairment of gait or range-of-motion. (MOV 2631 kb)

Supplementary Video 6

LDN-193189-treated, Ad.Cre-injected conditional caALK2 mouse shown at P30. Mild gait abnormality due to moderately decreased range of motion in knee and hip joints. (MOV 3027 kb)

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Yu, P., Deng, D., Lai, C. et al. BMP type I receptor inhibition reduces heterotopic ossification. Nat Med 14, 1363–1369 (2008).

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