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

Abstract

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.