The p53-miR17 family-Rankl axis bridges liver-bone communication.

Our study elucidates the crucial role of the liver in bone homeostasis through the p53-miR17 family (miR17-miR20/miR20-miR106/miR93-miR106)-Rankl axis. We demonstrate the enhanced hepatocyte Rankl expression in inflammaging conditions, such as aging, ovariectomized (OVX) mice, and elderly humans. Mice with hepatocyte-specific Rankl deletion exhibit significant resistance to bone mass loss associated with aging, lipopolysaccharide (LPS)-induced inflammation, or estrogen deficiency, compared with controls. Our study highlights hepatocytes as the primary source of Rankl in the liver and serum under these conditions. We identify the p53-miR17 family axis as a crucial regulator for hepatocyte Rankl expression, with p53 inhibiting the miR17 family transcription. Through bioinformatics analysis and in vitro validation, we identify Rankl mRNA as a direct target of the miR17 family. Targeting this axis via CasRx-mediated mRNA editing or miRNA interference significantly attenuates bone mass loss in mice. Our investigation underscores the pivotal significance and therapeutic potential of modulating the p53-miR17 family-Rankl axis in the treatment of inflammaging-associated osteoporosis.