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Updated: Jun 27, 2025

Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
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Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model

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Sclerostin blockade inhibits bone resorption through PDGF receptor signaling in osteoblast lineage cells

Cyril Thouverey, Pierre Apostolides, Julia Brun

    JCI Insight
    |May 7, 2024
    PubMed

    Insights

    Sclerostin-neutralizing antibodies (Scl-Abs) inhibit bone resorption by blocking platelet-derived growth factor receptor (PDGFR) signaling in osteoblast cells, independent of Wnt signaling.

    Area of Science:

    • Bone biology
    • Endocrinology
    • Cell signaling

    Background:

    • Sclerostin-neutralizing antibodies (Scl-Abs) promote bone formation via Wnt signaling but also inhibit bone resorption.
    • The mechanism behind Scl-Abs' sustained inhibition of bone resorption is not fully understood.
    • Sclerostin activates platelet-derived growth factor receptors (PDGFRs) in osteoblast lineage cells.

    Purpose of the Study:

    • To investigate the role of PDGFR signaling in the prolonged anticatabolic effects of Scl-Abs.
    • To elucidate the mechanism by which Scl-Abs inhibit osteoclast activity.

    Main Methods:

    • Inhibition of PDGFR signaling in osteoblast lineage cells in mice.
    • Analysis of M-CSF secretion and osteoclast activity.
    • Investigation of sclerostin-PDGFR complex formation in preosteoblasts.
    • Coculture assays with preosteoblasts and osteoclasts.

    Main Results:

    • Inhibition of PDGFR signaling in osteoblast lineage cells mediates the prolonged anticatabolic effects of Scl-Abs.
    • Sclerostin coactivates PDGFRs independently of Wnt/β-catenin signaling by forming a ternary complex with LRP6 and PDGFRs.
    • Scl-Abs prevent sclerostin-mediated PDGFR coactivation, reducing M-CSF upregulation and osteoclast activity.

    Conclusions:

    • PDGFR signaling inhibition is crucial for the sustained antiresorptive effects of Scl-Abs.
    • Sclerostin's interaction with LRP6 and PDGFRs provides a novel target for modulating bone resorption.
    • This mechanism explains the dissociation between anabolic and antiresorptive effects of Scl-Abs.
    Keywords:
    Bone biologyOsteoclast/osteoblast biologyOsteoporosisSignal transduction

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