Senescence impairs preosteoblast expansion and differentiation into functional osteoblasts,blunts their responses to bone formation-stimulating factors and stimulates their secretion of osteoclast-activating factors.Due to these adverse effects,preosteoblast senescence is a crucial target for the treatment of age-related bone loss;however,the underlying mechanism remains unclear.We found that mTORC1 accelerated preosteoblast senescence in vitro and in a mouse model.Mechanistically,mTORC1 induced a change in the membrane potential from polarization to depolarization,thus promoting cell senescence by increasing Ca2+influx and activating downstream NFAT/ATF3/p53 signaling.We further identified the sodium channel Scn1a as a mediator of membrane depolarization in senescent preosteoblasts.Scn1a expression was found to be positively regulated by mTORC1 upstream of C/EBPα,whereas its permeability to Na+was found to be gated by protein kinase A(PKA)-induced phosphorylation.Prosenescent stresses increased the permeability of Scn1a to Na+by suppressing PKA activity and induced depolarization in preosteoblasts.Together,our findings identify a novel pathway involving mTORC1,Scn1a expression and gating,plasma membrane depolarization,increased Ca2+influx and NFAT/ATF3/p53 signaling in the regulation of preosteoblast senescence.Pharmaceutical studies of the related pathways and agents might lead to novel potential treatments for age-related bone loss.

Academy of Orthopedics,Guangdong Province,Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases,Department of Spine Surgery,The Third Affiliated Hospital of Southern Medical University,Guangzhou,China;Department of Spine Surgery,Nanfang Hospital,Southern Medical University,Guangzhou,China;Department of Clinical Laboratory,The Third Affiliated Hospital of Southern Medical University,Guangzhou,China;Department of Cell Biology,School of Basic Medical Science,Southern Medical University,Guangzhou,China

[1]Ajuan Chen;Jian Jin;Shasha Cheng;Zezheng Liu;Cheng Yang;Qingjing Chen;Wenquan Liang;Kai Li;Dawei Kang;Zhicong Ouyang;Chenfeng Yao;Xiaochun Bai;Qingchu Li;Dadi Jin;Bin Huang-.mTORC1 induces plasma membrane depolarization and promotes preosteoblast senescence by regulating the sodium channel Scn1a)[J].骨研究（英文版）,2022(02):394-408

Scn1a,blunts,preosteoblasts,Na+was,Prosenescent,Na+by

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