Sclerostin inhibition alleviates breast cancer–induced bone metastases and muscle weakness
Eric Hesse, Saskia Schröder, Diana Brandt, Jenny Pamperin, Hiroaki Saito, Hanna Taipaleenmäki
Eric Hesse, Saskia Schröder, Diana Brandt, Jenny Pamperin, Hiroaki Saito, Hanna Taipaleenmäki
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Research Article Bone biology Oncology

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 osteoblast-mediated 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 cancer-bearing 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.

Authors

Eric Hesse, Saskia Schröder, Diana Brandt, Jenny Pamperin, Hiroaki Saito, Hanna Taipaleenmäki

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Figure 5

Treatment with an anti-sclerostin antibody reverses breast cancer–induced activation of NF-κB signaling and increased number of Pax7-positive cells.

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Treatment with an anti-sclerostin antibody reverses breast cancer–induce...
(A) Immunoblot analysis of phosphorylated IKKα and IKKβ (p-IKKα and p-IKKβ), phosphorylated NF-κBp65 (p-NF-κBp65), phosphorylated p38 (p-p38), and total p38 in the gastrocnemius (GAS) muscle of healthy nontreated mice (n = 5) and cancer-bearing mice treated with vehicle (n = 8) or Scl-Ab (n = 8). Actin was used as loading control. Representative samples are shown. (B) Immunoblot analysis of phosphorylated NF-κBp65 (p-NF-κBp65), phosphorylated p38 (p-p38) and total p38 in C2C12 myoblasts stimulated with vehicle (veh) or TGF-β1. Actin was used as loading control. Representative image of 6 independent experiments is shown. (C) Immunoblot analysis of phosphorylated NF-κBp65, p-p38, and total p38 in C2C12 cells treated with a control peptide or an NF-κB blocking peptide (NPD) and stimulated with vehicle or TGF-β1. Actin was used as loading control. Representative image of 4 independent experiments is shown. (D) Myogenin and MyoD mRNA expression was quantified by qRT-PCR in C2C12 cells after 10 days of myogenic differentiation (n = 4). (E) Pai1 mRNA expression was quantified in the GAS muscle from healthy nontreated mice (n = 5) and from cancer-bearing mice treated with vehicle (n = 8) or Scl-Ab (n = 8). (F) Immunohistochemical staining of Pax7 in the tibialis anterior (TA) muscle from healthy nontreated mice and from mice with bone metastases treated with vehicle or Scl-Ab. Scale bar: 50 μm (top row) and 100 μm (bottom row). (G) Quantification of Pax7-positive cells in the TA muscle from healthy nontreated mice (n = 5) and from mice with bone metastases treated with vehicle (n = 8) or Scl-Ab (n = 8). Data are presented as mean ± SEM. Two-tailed Student’s t test was used to compare 2 groups (D), and ANOVA followed by Tukey’s post hoc analysis was used to compare 3 or more groups (E and G); *P < 0.05, ***P < 0.001.