患者由来iPS細胞を用いた進行性骨化性線維異形成症における異所性骨化形成の解析

点击翻译按钮获取中文摘要

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by the mutation of ACVR1, which was symptomized by heterotopic ossification (HO) in soft tissues via endochondral ossification. Utilizing FOP patient-specific iPSCs, Activin A was identified as an evocator of HO by activating mTORC1 in our previous study. However, how the activated mTORC1 induces aberrant chondrogenesis is still unknown. According to the reported study, mTORC1 plays a special role in nutrient and growth factor response as well as stress to metabolic processes. Mitochondrial biogenesis is activated by mTORC1, which leads to upregulation of energy production by OXPHOS. Here we discussed that energy metabolism during aberrant chondrogenesis of FOP-iMSCs was studied to explore a new therapeutic strategy for FOP disease. In summary, we identified Activin A-induced chondrogenesis required OXPHOS as a major energy source and therefore the inhibition of OXPHOS could suppress chondrogenesis in vitro.　And utilizing FOP-ACVR1 mice, we demonstrated mitochondrial biogenesis was strongly activated during chondrogenesis of fibro/adipogenic precursors (FAPs), a small population of muscle-resident progenitors, reported as the cells of origin of pathological cartilage formation in soft tissue. Importantly, we also identified the inhibition of OXPHOS can suppress FAPs-derived chondrocyte differentiation in vivo. All these findings revealed the features of mitochondrial biogenesis and OXPHOS activity during the formation of heterotopic cartilage and will provide a novel perspective on FOP therapy.