1. The Akt-GSK3β and canonical NF-κB pathways are activated in Slc7a5-deficient osteoclasts.
The Akt-GSK3β and canonical NF-κB pathways are activated in Slc7a5-deficient osteoclasts. BMMs from Slc7a5fl/fl mice were retrovirally infected with Cre recombinase and subsequently stimulated with RANKL, followed by immunoblotting and densitometric quantification of (A to C) phosphorylation of Akt and GSK3β, (D to F) phosphorylation of IKKα/β and IκBα, and (G and H) abundance of p65. n = 4 mice per genotype. (I and J) BMMs from Slc7a5fl/fl mice were retrovirally infected with Cre recombinase and subsequently stimulated with RANKL in the presence or absence of Akt inhibitor X (I) or the IKK inhibitor BMS (J), followed by TRAP staining. n = 4 mice per genotype. All data were analyzed by the two-way ANOVA with Bonferroni and/or Dunnett post hoc test. **P < 0.01, significantly different from the value obtained in control cells. ##P < 0.01, significantly different from the value obtained in Slc7a5-deficient cells without inhibitors. (K) Model for LAT1-mediated control of osteoclast activation. The LAT1-mTORC1 axis (red dashed square) inhibits the activation of Akt, thus preventing GSK3β from stimulating the translocation of NFATc1 from the nucleus to the cytoplasm. LAT1-mTORC1 signaling also inhibits the activation of IKK and IκBα in osteoclasts, thus preventing the degradation of IκB and the nuclear translocation of the p65 and p50 subunits that constitute NF-κB. These actions repress the nuclear accumulation of NFATc1 and Nfatc1 expression, respectively, leading to the inhibition of NFATc1-dependent osteoclastic gene expression, thereby impeding osteoclastogenesis.
Kakeru Ozaki et al., Sci. Signal. 2019;12:eaaw3921
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