State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Translational Research Program of Pediatric Orthopedics, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Courant Institute of Mathematical Sciences, New York University, New York, NY, USA.
Cell Rep. 2021 Aug 17;36(7):109542. doi: 10.1016/j.celrep.2021.109542.
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.
特立帕肽是世界上应用最广泛的骨合成代谢药物，但它的细胞靶点仍不完全明确。Gli1 干骺端间充质祖细胞（MMPs）是出生后生长小鼠中成骨细胞的主要来源，但它们对特立帕肽的潜在反应尚不清楚。在这里，通过谱系追踪，我们表明特立帕肽刺激 MMPs 的增殖和成骨细胞分化。单细胞 RNA 测序揭示了 MMPs 之间的异质性，包括一个出乎意料的软骨细胞样成骨前体（COP）。COP 在所有细胞簇中表达最高水平的 Hedgehog（Hh）靶基因和胰岛素样生长因子 1 受体（Igf1r）。COP 还表达 Pth1r，并在特立帕肽处理后进一步上调 Igf1r。抑制 Hh 信号或从 MMPs 中缺失 Igf1r 可减弱特立帕肽的增殖和成骨作用。因此，该研究将 COP 确定为特立帕肽的一个靶点，其中 Hh 和胰岛素样生长因子（Igf）信号对于生长小鼠的骨合成代谢反应至关重要。
