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Published on: November 6, 2014

Myeloma cells suppress osteoblasts through sclerostin secretion

S Colucci, G Brunetti, A Oranger

    Blood Cancer Journal
    |July 26, 2012
    PubMed

    Insights

    Myeloma cells secrete sclerostin, a Wnt antagonist, inhibiting bone formation by reducing osteoblast activity. Blocking sclerostin restores osteoblast function, offering a potential therapeutic target for multiple myeloma bone disease.

    Area of Science:

    • Bone Biology
    • Oncology
    • Endocrinology

    Background:

    • Multiple myeloma (MM) bone disease is characterized by decreased osteoblast (OB) activity, partly due to Wnt signaling inhibitors.
    • Sclerostin, an osteocyte-expressed Wnt antagonist, is a key regulator of bone formation.

    Purpose of the Study:

    • To investigate the role of sclerostin expressed by myeloma cells in MM-associated bone disease.
    • To determine if targeting sclerostin can restore osteoblast function.

    Main Methods:

    • Co-culture of human myeloma cell lines (HMCLs) and bone marrow stromal cells (BMSCs) differentiated into OBs.
    • Assessment of OB-specific protein expression, mineralized nodule formation, and transcription factor activity.
    • Treatment with neutralizing anti-sclerostin antibodies and analysis of β-catenin, receptor activator of nuclear factor κ-B ligand (RANKL), and osteoprotegerin (OPG) levels.

    Main Results:

    • Myeloma cells express and secrete sclerostin.
    • Co-culture with HMCLs reduced OB function, including protein expression and mineralized nodule formation, and altered transcription factor expression (Fra-1, Fra-2, Jun-D).
    • Anti-sclerostin antibodies restored OB function, induced β-catenin nuclear accumulation, and normalized RANKL/OPG expression.

    Conclusions:

    • Sclerostin secreted by myeloma cells contributes to the suppression of bone formation in MM.
    • Targeting sclerostin may represent a therapeutic strategy to improve bone health in patients with multiple myeloma.

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