ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research
Maarten van DintherPeter Ten Dijke

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare disabling disease characterized by heterotopic ossification for which there is currently no treatment available. FOP has been linked recently to a heterozygous R206H mutation in the bone morphogenetic protein (BMP) type I receptor activin receptor-like kinase 2 (ALK2). Expression of the mutant ALK2-R206H receptor (FOP-ALK2) results in increased phosphorylation of the downstream Smad1 effector proteins and elevated basal BMP-dependent transcriptional reporter activity, indicating that FOP-ALK2 is constitutively active. FOP-ALK2-induced transcriptional activity could be blocked by overexpressing either of the inhibitory Smads, Smad6 or -7, or by treatment with the pharmacological BMP type I receptor inhibitor dorsomorphin. However, in contrast to wild-type ALK2, FOP-ALK2 is not inhibited by the negative regulator FKBP12. Mesenchymal cells expressing the FOP-ALK2 receptor are more sensitive to undergoing BMP-induced osteoblast differentiation and mineralization. In vivo bone formation was assessed by loading human mesenchymal stem cells (hMSCs) expressing the ALK2-R206H receptor onto calcium phosphate scaffolds and implantation in nude mice. Compared with control cells FOP-ALK2...Continue Reading

Citations

Mar 29, 2014·Hernia : the Journal of Hernias and Abdominal Wall Surgery·E M FennemaW J Mastboom
May 14, 2010·The Journal of Biological Chemistry·Gin-Ah SongHyun-Mo Ryoo
Feb 23, 2011·Current Osteoporosis Reports·Eileen M Shore, Frederick S Kaplan
Mar 18, 2011·Molecular Biology of the Cell·Long ZhangPeter Ten Dijke
Nov 2, 2012·Disease Models & Mechanisms·Frederick S KaplanEileen M Shore
Feb 14, 2012·Biochemical and Biophysical Research Communications·Long ZhangPeter ten Dijke
Oct 30, 2016·Proceedings of the National Academy of Sciences of the United States of America·Yohei HayashiShinya Yamanaka
Dec 21, 2017·Intractable & Rare Diseases Research·Zijuan QiJinxiang Han
Nov 7, 2019·Cells·José Antonio ValerFrancesc Ventura
Oct 8, 2019·Journal of Internal Medicine·S CederströmP Tornvall
Sep 10, 2020·International Journal of Molecular Sciences·Chen XieJijun Hao
Aug 27, 2019·F1000Research·Matthieu SchapiraRachel J Harding
Aug 3, 2016·Cold Spring Harbor Perspectives in Biology·Carl-Henrik Heldin, Aristidis Moustakas
Nov 3, 2016·Cold Spring Harbor Perspectives in Biology·Apirat Chaikuad, Alex N Bullock
Mar 29, 2018·International Journal of Molecular Sciences·Serena CappatoRenata Bocciardi
Mar 7, 2021·Biomedicines·Francesc VenturaGonzalo Sanchez-Duffhues
Nov 16, 2017·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Melissa LaBonty, Pamela C Yelick
Jun 17, 2021·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Oscar Will Towler, Eileen M Shore
May 19, 2021·The EMBO Journal·Anassuya RamachandranCaroline S Hill

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