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<p>Breast cancer (BC)-derived bone metastases colonize bone and drive severe bone degradation through complex interactions with bone-resorbing osteoclasts (OCs). Subsequent bone resorption liberates matrix-stored factors, such as TGF-β and calcium, which further stimulate tumor proliferation and exacerbate bone destruction. Myostatin (Mstn), a member of the TGF-β superfamily, is known to enhance OC differentiation and bone resorption in models of musculoskeletal disease; however, its role in BC-associated bone lesions and metastases remains unknown. Here, we demonstrate that bone metastases from BC patients express Mstn, predominantly localized at the osteoclast-rich bone–tumor interface. In vitro, both direct and indirect interactions between BC cells and OC precursors significantly increased OC formation and resorptive activity. Antibody-mediated blockade of Mstn attenuated these effects by inhibiting SMAD2 phosphorylation. In vivo, targeting Mstn in 4T1 and MDA-MB-231 murine models of BC-induced bone destruction resulted in elevated bone density, increased muscle mass, and reduced OC numbers compared to controls. Furthermore, anti-Mstn treatment decreased the burden of bone metastases in MDA-MB-231-bearing mice. Collectively, these findings identify Mstn as a previously unrecognized driver of BC-induced osteolysis and metastases, highlighting its potential as a therapeutic target in metastatic BC.</p>

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Pharmacological inhibition of myostatin effectively ameliorates osteolytic lesions in syngeneic and xenograft breast cancer mouse models

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月17日

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  • Julia Reinhardt,
  • Berno Dankbar,
  • Fabienne Geers,
  • Eugenie Werbenko,
  • Christiane Geyer,
  • Annalen Bleckmann,
  • Kerstin Menck,
  • Anne Grözinger,
  • Wolfgang Hartmann,
  • Joke Tio,
  • Carsten Höltke,
  • Anne Helfen,
  • Andreas Lodberg,
  • Rosa Al-Qasemi,
  • Denise Beckmann,
  • Sarah Bödecker,
  • Simon Kleimann,
  • Linda Wessendorf,
  • Deniz Wawersig,
  • Thomas Pap,
  • Corinna Wehmeyer

摘要

Breast cancer (BC)-derived bone metastases colonize bone and drive severe bone degradation through complex interactions with bone-resorbing osteoclasts (OCs). Subsequent bone resorption liberates matrix-stored factors, such as TGF-β and calcium, which further stimulate tumor proliferation and exacerbate bone destruction. Myostatin (Mstn), a member of the TGF-β superfamily, is known to enhance OC differentiation and bone resorption in models of musculoskeletal disease; however, its role in BC-associated bone lesions and metastases remains unknown. Here, we demonstrate that bone metastases from BC patients express Mstn, predominantly localized at the osteoclast-rich bone–tumor interface. In vitro, both direct and indirect interactions between BC cells and OC precursors significantly increased OC formation and resorptive activity. Antibody-mediated blockade of Mstn attenuated these effects by inhibiting SMAD2 phosphorylation. In vivo, targeting Mstn in 4T1 and MDA-MB-231 murine models of BC-induced bone destruction resulted in elevated bone density, increased muscle mass, and reduced OC numbers compared to controls. Furthermore, anti-Mstn treatment decreased the burden of bone metastases in MDA-MB-231-bearing mice. Collectively, these findings identify Mstn as a previously unrecognized driver of BC-induced osteolysis and metastases, highlighting its potential as a therapeutic target in metastatic BC.