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oai:repisalud.isciii.es:20.500.12105/131652025-06-17T09:41:02Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19616

00925njm 22002777a 4500 dc Sánchez-Duffhues, Gonzalo author Williams, Eleanor author Benderitter, Pascal author Orlova, Valeria author van Wijhe, Michiel author Garcia de Vinuesa, Amaya author Kerr, Georgina author Caradec, Josselin author Lodder, Kirsten author de Boer, Hetty C author Goumans, Marie-José author Eekhoff, Elisabeth M W author Morales-Piga, Antonio author Bachiller-Corral, Javier author Koolwijk, Pieter author Bullock, Alex N author Hoflack, Jan author Ten Dijke, Peter author 2019-11 Fibrodysplasia ossificans progressiva (FOP) is an extremely rare congenital form of heterotopic ossification (HO), caused by heterozygous mutations in the activin A type I receptor (ACVR1), that encodes the bone morphogenetic protein (BMP) type I receptor ALK2. These mutations enable ALK2 to induce downstream signaling in response to activins, thereby turning them into bone-inducing agents. To date, there is no cure for FOP. The further development of FOP patient-derived models may contribute to the discovery of novel biomarkers and therapeutic approaches. Nevertheless, this has traditionally been a challenge, as biopsy sampling often triggers HO. We have characterized peripheral blood-derived endothelial colony-forming cells (ECFCs) from three independent FOP donors as a new model for FOP. FOP ECFCs are prone to undergo endothelial-to-mesenchymal transition and exhibit increased ALK2 downstream signaling and subsequent osteogenic differentiation upon stimulation with activin A. Moreover, we have identified a new class of small molecule macrocycles with potential activity against ALK2 kinase. Finally, using FOP ECFCs, we have selected OD36 and OD52 as potent inhibitors with excellent kinase selectivity profiles that potently antagonize mutant ALK2 signaling and osteogenic differentiation. We expect that these results will contribute to the development of novel ALK2 clinical candidates for the treatment of FOP. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. JBMR Plus. 2019 Oct 7;3(11):e10230. 10.1002/jbm4.10230 2473-4039 JBMR Plus 31768489 http://hdl.handle.net/20.500.12105/13165 Bone Morphogenetic Protein Endothelial Endothelial‐To‐Mesenchymal Transition Fibrodysplasia Ossificans Progressiva Osteoblast; Tgf‐Β Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva-Derived Endothelial Cells