An mTOR Signaling Modulator Suppressed Heterotopic Ossification of Fibrodysplasia Ossificans Progressiva

• DOI: 10.1016/j.stemcr.2018.10.007
• Publication Date: 2018-11-01T14:43:51Z
• Authors: Kyosuke Hino; Chengzhu Zhao; Kazuhiko Horigome; Megumi Nishio; Yasue Okanishi; Sanae Nagata; Shingo Komura; Yasuhiro Yamada; Junya Toguchida; Akira Ohta; Makoto Ikeya
• Keywords: Fibrodysplasia Ossificans Progressiva; Endochondral ossification; Chondrogenesis

Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disorder characterized by extraskeletal bone formation through endochondral ossification. FOP patients harbor gain-of-function mutations in ACVR1 (FOP-ACVR1), type I receptor for morphogenetic proteins. Despite numerous studies, no drugs have been approved FOP. Here, we developed high-throughput screening (HTS) system focused on the constitutive activation of FOP-ACVR1 utilizing chondrogenic ATDC5 cell line that stably expresses FOP-ACVR1. After HTS 5,000 small-molecule compounds, identified two hit compounds are effective at suppressing enhanced chondrogenesis patient-derived induced pluripotent stem cells (FOP-iPSCs) suppressed heterotopic ossification (HO) multiple model mice, including transgenic mice HO FOP-iPSCs. Furthermore, revealed one an mTOR signaling modulator indirectly inhibits signaling. Our results demonstrate these could contribute to future drug repositioning mechanistic analysis