mTORC1 induces plasma membrane depolarization and promotes preosteoblast senescence by regulating the sodium channel Scn1a

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.

Tumor burden score and alpha-fetoprotein level predict prognosis of patients with unresectable hepatocellular carcinoma treated with tyrosine kinase inhibitor and anti-PD-1 antibody

Background:Tyrosine kinase inhibitors(TKIs)and anti-PD-1 antibodies in combination provide survival benefits for patients with unresectable hepatocellular carcinoma(uHCC).However,the tool used to determine which patients likely benefit most from this treatment strategy has not been reported.We sought to develop a prognostic scoring system based on tumor burden score(TBS)and alpha-fetoprotein(AFP)to predict the long-term prognosis of uHCC treated with TKIs and anti-PD-1 antibodies.Methods:Data on patients with uHCC treated with TKIs and anti-PD-1 antibodies from multiple centers were collected.The prognostic accuracy of TBS,AFP,Barcelona Clinic Liver Cancer(BCLC),and CTA(Combined TBS and AFP)for 2-year progression-free survival(PFS)and overall survival(OS)was evaluated.Results:Overall,278 patients with uHCC treated with TKIs and anti-PD-1 antibodies were enrolled,including 48 BCLC-B and 230 BCLC-C HCC patients.CTA(AUC?0.721 and 0.683)outperformed TBS(AUC?0.680 and 0.621),AFP(AUC?0.606 and 0.594),and BCLC staging(AUC?0.551 and 0.555)in predicting PFS and OS.The 2-year PFS and OS for low CTA(low TBS/low AFP)were 65.7%and 94.4%,respectively,which were significantly higher than 21.6%and 44.9%(p<0.001 and p?0.002),respectively,for intermediate CTA(low TBS/high AFP or high TBS/low AFP)and 8.7%and 12.1%(both p<0.001),respectively,for high CTA(high TBS/high AFP).Multivariable Cox regression analysis indicated that CTA grading was an independent prognostic factor for PFS and OS(referent:low CTA;intermediate CTA,HR 2.87 and 7.17;high CTA,HR 5.52 and 10.31,respectively).Conclusions:CTA grading is an accurate tool for stratifying the prognosis of uHCC treated with TKIs and anti-PD-1 antibodies and may help determine which patients may benefit more from this treatment strategy.