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.D...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 Ca^(2+)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 Ca^(2+)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 agerelated bone loss.展开更多
基金supported by grants 82172507 (B.H.), 81700783 (B.H.)and 81672120 (D.J.) from the National Natural Science Foundation of China+1 种基金2019A1515011876 (B.H.) and 2018A030313937 (Z.L.) from the Guangdong Natural Science Fund Management Committee202002030176 (B.H.) from the Guangzhou Municipal Science and Technology Bureau
文摘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 Ca^(2+)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 Ca^(2+)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 agerelated bone loss.
