Gli1+ progenitors mediate bone anabolic function of teriparatide via Hh and Igf signaling.

Yu Shi,Ling Qin,Ling Ye,Lutian Yao,Fanxin Long,Feng Lou,Jianquan Chen,Guangxu He,Xueyang Liao,Bei Yin,James Y Long

doi:10.1016/j.celrep.2021.109542

Abstract

SUMMARYTeriparatide 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.

Highlights

Osteoblasts (OBs), the chief bone-making cells, are replenished throughout life in mammals, but their origin in postnatal life remains to be fully elucidated (Long, 2011)
Micro-computed tomography imaging and quantification of the cancellous bone in the distal femur confirmed that teriparatide caused a notable increase in bone mass (BV/TV), trabecular thickness (Tb.th), and trabecular bone number (Tb.N), coupled with decreased trabecular spacing (Tb.Sp), compared to the vehicle injection (Figure S1)
When the bone sections were examined for tdTomato marking the Gli1lineage cells, we found that teriparatide greatly increased the number of tdTomato+ cells within the metaphyseal trabecular bone region (Figures 1A–1C)

Summary

Introduction

Osteoblasts (OBs), the chief bone-making cells, are replenished throughout life in mammals, but their origin in postnatal life remains to be fully elucidated (Long, 2011). Lineage-tracing experiments have identified the Gli1-positive metaphyseal mesenchymal progenitors (MMPs) as a major source for trabecular osteoblasts in the long bones of mice up to four months of age (Shi et al, 2017). MMPs give rise to the leptin receptor-positive (LepR+) bone marrow stromal cells, which in turn have been shown to produce osteoblasts in adult mice progressively with age (Mizoguchi et al, 2014; Zhou et al, 2014a). MMPs are immediate osteoblast precursors in the growing mice but may provide long-term osteoprogenitors persisting in the bone marrow later in life. Teriparatide was shown to increase both number and osteoblast differentiation of a Sox9-positive osteoprogenitor population located within the primary spongiosa of growing mice (Balani et al, 2017). Because previous immunostaining did not detect Sox protein in MMPs, it is not known whether MMPs would respond to the anabolic regimen of teriparatide (Shi et al, 2017)

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