Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G --> A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.

Macrophages are the dominant infiltrating cells that respond rapidly to biomaterial implantation in soft and hard tissues. These cells and their fused morphologic variants, multinucleated giant cells or foreign body giant cells, usually remain at biomaterial-tissue interfaces for the lifetime of the device in vivo. As a component of the immune system, macrophage activities are closely related to immune responses, inflammation and foreign body responses. However, macrophages also mediate biodegradation of bioresorbable materials via phagocytosis and extracellular degradation. In addition, macrophages are essential for effective tissue regeneration as they regulate the recruitment, proliferation and differentiation of target cells, such as fibroblasts, osteoblasts, endothelial cells and keratinocytes during healing processes.

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Background: Mutations in the ALK2 kinase cause extraskeletal bone formation.Results: We solved the structure of ALK2 in complex with the inhibitor FKBP12.Conclusion: Disease mutations break critical interactions that stabilize the inactive ALK2-FKBP12 complex leading to kinase activation.Significance: We offer an explanation for the effects of mutation and a structural template for the design of small molecule inhibitors.

Growth factor signaling pathways are tightly regulated by phosphorylation and include many important kinase targets of interest for drug discovery. Small molecule inhibitors of the bone morphogenetic protein (BMP) receptor kinase ALK2 (ACVR1) are needed urgently to treat the progressively debilitating musculoskeletal disease fibrodysplasia ossificans progressiva (FOP). Dorsomorphin analogues, first identified in zebrafish, remain the only BMP inhibitor chemotype reported to date. By screening an assay panel of 250 recombinant human kinases we identified a highly selective 2-aminopyridine-based inhibitor K02288 with in vitro activity against ALK2 at low nanomolar concentrations similar to the current lead compound LDN-193189. K02288 specifically inhibited the BMP-induced Smad pathway without affecting TGF-β signaling and induced dorsalization of zebrafish embryos. Comparison of the crystal structures of ALK2 with K02288 and LDN-193189 revealed additional contacts in the K02288 complex affording improved shape complementarity and identified the exposed phenol group for further optimization of pharmacokinetics. The discovery of a new chemical series provides an independent pharmacological tool to investigate BMP signaling and offers multiple opportunities for pre-clinical development.

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