Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva.

Currently, no effective therapies exist for fibrodysplasia ossificans progressiva (FOP), a rare congenital syndrome in which heterotopic bone is formed in soft tissues owing to dysregulated activity of the bone morphogenetic protein (BMP) receptor kinase ALK2 (also known as ACVR1). From a screen of known biologically active compounds, we identified saracatinib as a potent ALK2 kinase inhibitor. In enzymatic and cell-based assays, saracatinib preferentially inhibited ALK2, compared with other receptors of the BMP/TGF-ß signaling pathway, and induced dorsalization in zebrafish embryos consistent with BMP antagonism. We further tested the efficacy of saracatinib using an inducible ACVR1Q207D-transgenic mouse line, which provides a model of heterotopic ossification (HO), as well as an inducible ACVR1R206H-knockin mouse, which serves as a genetically and physiologically faithful FOP model. In both models, saracatinib was well tolerated and potently inhibited the development of HO, even when administered transiently following soft tissue injury. Together, these data suggest that saracatinib is an efficacious clinical candidate for repositioning in FOP treatment, offering an accelerated path to clinical proof-of-efficacy studies and potentially significant benefits to individuals with this devastating condition.

Twisted gastrulation, a bone morphogenetic protein agonist/antagonist, is not required for post-natal skeletal function.

Twisted gastrulation (Tsg) is a secreted glycoprotein that binds bone morphogenetic proteins (BMP)-2 and -4 and can display both BMP agonist and antagonist functions. Tsg promotes BMP-mediated endochondral ossification, but its activity in adult bone is not known. We created tsg null mice and examined the consequences of the tsg deletion on the skeleton in vivo and on osteoblast function in vitro. Analysis of the skeletal phenotype of 4-week-old tsg null mice revealed a 40% decrease in trabecular bone volume, but osteoblast and osteoclast number, and bone formation and resorption were not affected. The phenotype was transient, and at 7 weeks of age tsg null mice were not different from control wild-type mice. The decreased trabecular bone is congruent with a defect in endochondral bone formation. In osteoblasts isolated from tsg null mice, tsg gene inactivation decreased the BMP-2 stimulatory effects on osteocalcin expression and alkaline phosphatase activity, indicating that in the bone microenvironment endogenous Tsg enhances BMP activity. Accordingly, tsg null cells displayed impaired BMP signaling. These results were confirmed by Tsg down-regulation in primary osteoblasts from wild-type mice using RNA interference. In conclusion, endogenous Tsg is required for normal BMP activity in osteoblastic cells in vitro, but it plays a minor role in the regulation of adult bone homeostasis in vivo.