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Gli1+ Progenitors Mediate Glucocorticoid-Induced Osteoporosis In Vivo
Puying Yang1, Fangyuan Shen1, Chengjia You1
1State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
Abstract:
For a wide range of chronic autoimmune and inflammatory diseases in both adults and children, synthetic glucocorticoids (GCs) are one of the most effective treatments. However, besides other adverse effects, GCs inhibit bone mass at multiple levels, and at different ages, especially in puberty. Although extensive studies have investigated the mechanism of GC-induced osteoporosis, their target cell populations still be obscure. Here, our data show that the osteoblast subpopulation among Gli1+ metaphyseal mesenchymal progenitors (MMPs) is responsive to GCs as indicated by lineage tracing and single-cell RNA sequencing experiments. Furthermore, the proliferation and differentiation of Gli1+ MMPs are both decreased, which may be because GCs impair the oxidative phosphorylation(OXPHOS) and aerobic glycolysis of Gli1+ MMPs. Teriparatide, as one of the potential treatments for GCs in bone mass, is sought to increase bone volume by increasing the proliferation and differentiation of Gli1+ MMPs in vivo. Notably, our data demonstrate teriparatide ameliorates GC-caused bone defects by targeting Gli1+ MMPs. Thus, Gli1+ MMPs will be the potential mesenchymal progenitors in response to diverse pharmaceutical administrations in regulating bone formation.
Insights
Glucocorticoids (GCs) reduce bone mass by affecting specific bone cells. This study identifies Gli1+ metaphyseal mesenchymal progenitors (MMPs) as key targets, showing teriparatide can reverse GC-induced bone loss by acting on these cells.
Area of Science:
- Bone Biology
- Endocrinology
- Cellular Metabolism
Background:
- Synthetic glucocorticoids (GCs) are effective treatments for inflammatory diseases but cause significant bone loss (osteoporosis).
- The precise cellular mechanisms and target populations responsible for GC-induced bone loss, particularly during skeletal development, remain incompletely understood.
- Identifying specific progenitor cells affected by GCs is crucial for developing targeted therapeutic strategies.
Purpose of the Study:
- To identify the specific progenitor cell populations targeted by glucocorticoids (GCs) in the bone microenvironment.
- To elucidate the cellular and molecular mechanisms underlying GC-induced inhibition of bone formation.
- To evaluate the efficacy of teriparatide in mitigating GC-induced bone defects by targeting identified progenitor cells.
Main Methods:
- Utilized lineage tracing and single-cell RNA sequencing to identify GC-responsive cells within metaphyseal mesenchymal progenitors (MMPs).
- Assessed the impact of GCs on the proliferation, differentiation, oxidative phosphorylation (OXPHOS), and aerobic glycolysis of Gli1+ MMPs.
- Investigated the therapeutic effect of teriparatide on GC-induced bone loss in vivo, focusing on Gli1+ MMPs.
Main Results:
- Identified a subpopulation of osteoblasts within Gli1+ metaphyseal mesenchymal progenitors (MMPs) as directly responsive to GCs.
- Demonstrated that GCs decrease the proliferation and differentiation of Gli1+ MMPs, potentially by impairing their oxidative phosphorylation and aerobic glycolysis.
- Showed that teriparatide effectively ameliorates GC-induced bone defects by targeting and modulating the function of Gli1+ MMPs.
Conclusions:
- Gli1+ metaphyseal mesenchymal progenitors (MMPs) are a critical target cell population mediating glucocorticoid-induced bone loss.
- GCs disrupt the metabolic function (OXPHOS and glycolysis) of Gli1+ MMPs, leading to reduced bone formation.
- Teriparatide represents a promising therapeutic agent for glucocorticoid-induced osteoporosis by specifically targeting Gli1+ MMPs to restore bone volume.
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