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Study Provides Insight Into Bone-Overgrowth Disease

Last Updated: November 19, 2009.

In patients with fibrodysplasia ossificans progressiva, a mutation in the ACVR1 receptor appears to promote cartilage formation by inducing bone morphogenetic protein signaling, according to research published in the November issue of the Journal of Clinical Investigation.

THURSDAY, Nov. 19 (HealthDay News) -- In patients with fibrodysplasia ossificans progressiva (FOP), a mutation in the ACVR1 receptor appears to promote cartilage formation by inducing bone morphogenetic protein (BMP) signaling, according to research published in the November issue of the Journal of Clinical Investigation.

Qi Shen, Ph.D., of the University of Pennsylvania School of Medicine in Philadelphia, and colleagues write that patients with the classic presentation of FOP -- in which extraskeletal bone growth develops -- were found to have mutations in the activin A receptor, type I (ACVR1), which encodes a BMP receptor.

In the new research, the authors found that this R206H ACVR1 mutation triggers BMP signaling without requiring BMP to start the signaling cascade. The ACVR1 mutant appears to lead to impaired ACVR1-FKBP1A binding, resulting in leaky receptor activation in the absence of ligand, they write. In zebrafish embryos (a model of BMP signaling), introducing the mutant ACVR1 RNA caused increased ventralization due to BMP-independent overactivation of BMP signaling.

"These findings have practical implications in developing model systems for testing new pharmacologic approaches for blocking this renegade receptor," the authors write. "Finally, this study provides insight into a signaling pathway that regulates skeletal morphogenesis and also that, when dysregulated in a specific manner, orchestrates the promiscuous and ectopic chondroosseous differentiation of soft connective tissue into a disabling second skeleton of heterotopic bone."

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