Towards targeting overactive BMP signaling in Fibrodysplasia Ossificans Progressiva
AbstractFibrodysplasia Ossificans Progressiva (FOP) is a rare monogenetic disorder in which patients develop heterotopic ossification (HO). A heterozygous mutation in BMP type I receptor ALK2 results in hyper-sensitized BMP signaling. The aim of this study is to identify small molecules which can selectively inhibit this overactive BMP pathway. Thirteen FDA-approved small molecules were tested on their effect on BMP6-induced target gene expression, alkaline phosphatase activity and mineralization in KS483 cells. We identified cryptotanshinone as a small molecule able to inhibit BMP signaling. In conclusion, cryptotanshinone could be a novel small molecule inhibitor of the overactive BMP signaling pathway in FOP.
Pignolo, R.J., Shore, E.M., Kaplan, F.S. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet journal of rare diseases 6, 80 (2011).
Shore, E.M., et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nature Genetics 38, 5 (2006), 525-7.
Hatsell, S.J. et al. Acvr1r206h receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin a. Science translational medicine 7, 303 (2015).
de Gorter, D.J.J., et al. Deregulated bone morphogenetic protein receptor signaling underlies fibrodysplasia ossificans progressive. Current pharmateutical design 18, 57 (2012), 4087-92
Shimono, K., et al. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists. Nature medicine 17, 4 (2011), 454-60.
Yu, P.B., et al. BMP type I receptor inhibition reduces heterotopic [corrected] ossification. Nature medicine 14,12 (2008), 1363-9.
Mohedas, A.H., et al. Development of an ALK2-biased BMP type I receptor kinase inhibitor. ACS chemical biology 8, 6 (2013), 1291-302.
Vogt, J., Ryan T., Gopal P.S. The specificities of small molecule inhibitors of the TGFβ and BMP pathways. Cellular signalling 23, 11 (2011), 1831-42
Shore, E.M., Kaplan, F.S. Inherited human diseases of heterotopic bone formation. Nature Reviews Rheumatology 6, 9 (2010), 518-27 [Adjusted]
Kim, M-J., et al. Cryptotanshinone induces ER stress-mediated apoptosis in HepG2 and MCF7 cells. Apoptosis 1, 3 (2012), 248-57.
Bu, X. et al. Cryptotanshinone for preventing and alleviating alzheimer's disease. Patent WO 2002060435 A1. 8 Aug 2002
Li, X., et al. Cryptotanshinone inhibits LPS-induced proinflammatory mediators via TLR4 and TAK1 signaling pathway. International immunopharmacology 11,11 (2011), 1871-6.
Medici, D., et al. Conversion of vascular endothelial cells into multipotent stem-like cells. Nature medicine 16, 12 (2010), 1400-6.
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