Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness

Abstract

Breast cancer bone metastases often cause a debilitating incurable condition with osteolytic lesions, muscle weakness, and a high mortality. Current treatment comprises chemotherapy, irradiation, surgery, and antiresorptive drugs that restrict but do not revert bone destruction. In hormone receptor-negative breast cancer cell lines and human breast cancer tissue, we identified the expression of sclerostin, a soluble Wnt inhibitor that represses osteoblast differentiation and bone formation. In mice with breast cancer bone metastases, pharmacological inhibition of sclerostin using an anti-sclerostin antibody (Scl-Ab) reduced the metastatic burden. Furthermore, sclerostin inhibition prevented cancer-induced bone destruction by augmenting osteoblastmediated bone formation and by reducing osteoclast-dependent bone resorption. During advanced disease, NF-κB and p38 signaling was increased in muscles in a TGF-β1-dependent manner, causing muscle fiber atrophy, muscle weakness, and tissue regeneration with an increase in Pax7-positive satellite cells. Scl-Ab treatment restored NF-κB and p38 signaling, the abundance of Pax7-positive cells, and muscle function. These effects improved the health and expanded the life span of cancerbearing mice. Together, these results demonstrate that pharmacological inhibition of sclerostin reduces bone metastatic burden and muscle weakness, with a prolongation of survival time. This might provide novel options for treating musculoskeletal complications in breast cancer patients.