Neofunction of ACVR1 in Fibrodysplasia Ossificans Progressiva

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2015 Dec 2

PMID 26621707

Citations 165

Authors

Kyosuke Hino

Makoto Ikeya

Kazuhiko Horigome

Yoshihisa Matsumoto

Hayao Ebise

Megumi Nishio

Kazuya Sekiguchi

Mitsuaki Shibata

Sanae Nagata

Shuichi Matsuda

Junya Toguchida

Affiliations

Soon will be listed here.

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by extraskeletal bone formation through endochondral ossification. FOP patients harbor point mutations in ACVR1 (also known as ALK2), a type I receptor for bone morphogenetic protein (BMP). Two mechanisms of mutated ACVR1 (FOP-ACVR1) have been proposed: ligand-independent constitutive activity and ligand-dependent hyperactivity in BMP signaling. Here, by using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs), we report a third mechanism, where FOP-ACVR1 abnormally transduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling but not BMP signaling. Activin-A enhanced the chondrogenesis of induced mesenchymal stromal cells derived from FOP-iPSCs (FOP-iMSCs) via aberrant activation of BMP signaling in addition to the normal activation of TGF-β signaling in vitro, and induced endochondral ossification of FOP-iMSCs in vivo. These results uncover a novel mechanism of extraskeletal bone formation in FOP and provide a potential new therapeutic strategy for FOP.

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