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Sclerostin inhibition alleviates breast cancer–induced bone metastases and muscle weakness
Eric Hesse, … , Hiroaki Saito, Hanna Taipaleenmäki
Eric Hesse, … , Hiroaki Saito, Hanna Taipaleenmäki
Published April 9, 2019
Citation Information: JCI Insight. 2019;4(9):e125543. https://doi.org/10.1172/jci.insight.125543.
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Research Article Bone biology Oncology

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

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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 1

Breast cancer–derived sclerostin inhibits Wnt signaling in osteoblasts.

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Breast cancer–derived sclerostin inhibits Wnt signaling in osteoblasts.
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(A and B) Calvarial cells were differentiated into osteoblasts in the presence of control medium or cancer-conditioned medium (CM) collected from MDA-MB-231 metastatic breast cancer cells. Osteoblast differentiation was determined by quantification of Runx2 and osteocalcin (Ocn) gene expression (A) and by alizarin red S staining (B) (n = 4 independent experiments). (C) Calvarial osteoblasts were cultured in the presence of the indicated amount of MDA-MB-231–derived CM. Wnt signaling activity was determined by TOPflash reporter assay (n = 4 independent experiments). (D) Sclerostin mRNA expression was quantified in nonmetastatic MCF-7 and metastatic MDA-MB-231 breast cancer cells by qRT-PCR (n = 6 independent experiments). (E) SOST mRNA expression was analyzed in breast cancer tissue from 48 patients. Proportion of sclerostin-positive and sclerostin-negative tissue samples is shown for all patients and for triple-negative (ER–, PR–, HER–) and in hormone receptor–negative (ER–, PR–, HER+) patients. All, n = 48; ER–, PR–, HER-, n = 9; ER–, HER–, HER+, n = 7. (F) Wnt signaling activity in calvarial osteoblasts cultured with control medium or with CM from MDA-MB-231 cells transfected with scrambled control siRNA (si-Ctrl CM) or siRNA against sclerostin (si-Sclerostin CM) (n = 6 independent experiments). (G) Wnt signaling activity in calvarial osteoblasts isolated from mice heterozygous for the Lrp5 mutation G171V (Lrp5-G171V+/T) and from control littermates (Lrp5-G171V+/+) stimulated with control medium or cancer CM (n = 4 independent experiments). Data are presented as mean ± SEM. Two-tailed Student’s t test was used to compare 2 groups (A and D), and ANOVA followed by Tukey’s post hoc analysis was used to compare 3 or more groups (C, F, and G); *P < 0.05, **P < 0.01, ***P < 0.001.

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