Abstract
ABSTRACTFibrodysplasia 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.
Highlights
H eterotopic ossification (HO) is a musculoskeletal disorder characterized by bone formation at extraskeletal sites, such as soft tissues and joints
Because endothelial-to-mesenchymal transition (EndMT) is induced in response to inflammation, we investigated whether control and Fibrodysplasia ossificans progressiva (FOP) endothelial colony-forming cells (ECFCs) display a mesenchymal phenotype in response to the proinflammatory cytokine tumor necrosis factor (TNF)-α
FOP ECFCs recapitulate the pathogenic mechanisms underlying FOP, in particular, the induction of Smad1/5-mediated signaling by activin A, consistent with recent publications.[4,5] Noteworthy, such ALK2 neofunction in FOP ECFCs is sensitive to inhibitors of ALK2
Summary
H eterotopic ossification (HO) is a musculoskeletal disorder characterized by bone formation at extraskeletal sites, such as soft tissues and joints. 2,000,000 individuals) associated with mutations in the activin A type I receptor (ACVR1) gene, encoding the BMP type I receptor kinase ALK2.(1) Based on overexpression studies, early publications suggested that the mutant ALK2 receptor becomes hypersensitive to classical BMP ligands, or even constitutively active because of the impaired interaction with the type I receptor inhibitor FKBP12,(2) which led to the development of BMP type 1 of 13 n. I receptor kinase inhibitors to prevent ALK2 downstream signaling.[3] Two recent publications have shown that the recurrent ACVR1 c.617G > A (ALK2 R206H) mutation enables ALK2 to transduce downstream signaling through the BMP-specific Smad1/5/8 pathway in response to activins,(4,5) a subset of ligands of the TGF-β family, which normally induce Smad2/3 signaling via ALK4. Broad-spectrum anti-inflammatories are commonly used to ameliorate flare-ups, but demonstrate little benefit
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