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Title: Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva
Authors: Hino, Kyosuke
Horigome, Kazuhiko
Nishio, Megumi
Komura, Shingo
Nagata, Sanae
Zhao, Chengzhu
Jin, Yonghui  kyouindb  KAKEN_id
Kawakami, Koichi
Yamada, Yasuhiro
Ohta, Akira
Toguchida, Junya
Ikeya, Makoto  kyouindb  KAKEN_id
Author's alias: 日野, 恭介
戸口田, 淳也
池谷, 真
Issue Date: 1-Sep-2017
Publisher: American Society for Clinical Investigation
Journal title: Journal of Clinical Investigation
Volume: 127
Issue: 9
Start page: 3339
End page: 3352
Abstract: Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient–derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6, 809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of mesenchymal stromal cells derived from FOP-iPSCs (FOP-iMSCs). Two different HO mouse models, an FOP model mouse expressing FOP-ACVR1 and an FOP-iPSC–based HO model mouse, revealed critical roles for mTOR signaling in vivo. Moreover, we identified ENPP2, an enzyme that generates lysophosphatidic acid, as a linker of FOP-ACVR1 and mTOR signaling in chondrogenesis. These results uncovered the crucial role of the Activin-A/FOP-ACVR1/ENPP2/mTOR axis in FOP pathogenesis.
Description: FOPにおける骨化を抑える方法の発見 --FOPの異所性骨形成のシグナル伝達メカニズムの解明--. 京都大学プレスリリース. 2017-08-01.
Rights: The JCI is an open access journal. All research content is freely available immediately upon publication, and all articles published in the JCI are deposited in PubMed Central (PMC). Users are allowed to read, download, copy, distribute, print, search, or link to the full texts of the articles under the "fair use" limitations of US copyright law.
URI: http://hdl.handle.net/2433/226666
DOI(Published Version): 10.1172/JCI93521
PubMed ID: 28758906
Related Link: https://www.kyoto-u.ac.jp/ja/research-news/2017-08-01
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