GSE169560
Gli1+ progenitors mediate bone anabolic function of teriparatide via Hh and Igf signaling
Teriparatide, a bioactive fragment of human parathyroid hormone (PTH), is the most widely prescribed bone anabolic drug in the world, but its cellular targets remain incompletely defined.  The Gli1+ metaphyseal mesenchymal progenitors (MMPs) are a main source for osteoblasts in postnatal growing mice, but their potential response to teriparatide is unknown.  Here, by lineage tracing we find that teriparatide stimulates both proliferation and osteoblast differentiation of MMPs.  Single-cell RNA sequencing reveals heterogeneity among MMPs including a chondrocyte-like osteoprogenitor (herein COP) population that expands in response to teriparatide.  COPs express the highest level of Hedgehog (Hh) target genes and the insulin-like growth factor receptor Igf1r.  Inhibition of Hh signaling, or selective deletion of Igf1r in MMPs diminishes the proliferative and osteogenic effects of teriparatide.  The study therefore identifies MMPs as teriparatide target cells wherein Hh and Igf signaling are critical for osteoblast production. Overall design: Examination of the heterogeneity alteration of Gli1+ cells with or without teriparatide treatment.