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Shi, Yu; Liao, Xueyang; Long, James Y.; Yao, Lutian; Chen, Jianquan; Yin, Bei; Lou, Feng; He, Guangxu; Ye, Ling; Qin, Ling; Long, Fanxin
Cell reports, 08/2021, Letnik: 36, Številka: 7Journal Article
Teriparatide 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 show that teriparatide stimulates both proliferation and osteoblast differentiation of MMPs. Single-cell RNA sequencing reveals heterogeneity among MMPs, including an unexpected chondrocyte-like osteoprogenitor (COP). COP expresses the highest level of Hedgehog (Hh) target genes and the insulin-like growth factor 1 receptor (Igf1r) among all cell clusters. COP also expresses Pth1r and further upregulates Igf1r upon teriparatide treatment. Inhibition of Hh signaling or deletion of Igf1r from MMPs diminishes the proliferative and osteogenic effects of teriparatide. The study therefore identifies COP as a teriparatide target wherein Hh and insulin-like growth factor (Igf) signaling are critical for the osteoanabolic response in growing mice. Display omitted •Teriparatide promotes proliferation and osteoblast differentiation of Gli1+ progenitors•scRNA-seq uncovers chondrocyte-like osteoprogenitors (COPs) among Gli1+ progenitors•COPs are target cells of teriparatide•Hh and Igf signaling in Gli1+ progenitors mediates the anabolic effect of teriparatide Gli1+ metaphyseal mesenchymal progenitors (MMPs) are a main source for osteoblasts in postnatal mice. Through single-cell RNA sequencing, Shi et al. find a chondrocyte-like osteoprogenitor (COP) among MMPs. COP is a target of teriparatide, the mainstay of bone anabolic therapy, and requires Hh and Igf signaling for bone formation.
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