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

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Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness. / Hesse, Eric; Schröder, Saskia; Brandt, Diana; Pamperin, Jenny; Saito, Hiroaki; Taipaleenmäki, Hanna.

in: JCI INSIGHT, Jahrgang 5, 09.04.2019.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Hesse, E, Schröder, S, Brandt, D, Pamperin, J, Saito, H & Taipaleenmäki, H 2019, 'Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness', JCI INSIGHT, Jg. 5. https://doi.org/10.1172/jci.insight.125543

APA

Hesse, E., Schröder, S., Brandt, D., Pamperin, J., Saito, H., & Taipaleenmäki, H. (2019). Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness. JCI INSIGHT, 5. https://doi.org/10.1172/jci.insight.125543

Vancouver

Hesse E, Schröder S, Brandt D, Pamperin J, Saito H, Taipaleenmäki H. Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness. JCI INSIGHT. 2019 Apr 9;5. https://doi.org/10.1172/jci.insight.125543

Bibtex

@article{6fa093a2ae55474eba1ee42227a2ae2b,
title = "Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness",
abstract = "Breast cancer bone metastases often cause a debilitating non-curable condition with osteolytic lesions, muscle weakness and a high mortality. Current treatment comprises chemotherapy, irradiation, surgery and anti-resorptive drugs that restrict but do not revert bone destruction. In metastatic breast cancer cells, we determined 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 metastases without tumor cell dissemination to other distant sites. Sclerostin inhibition prevented the cancer-induced bone destruction by augmenting osteoblast-mediated bone formation and 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 ultimately muscle function. These effects improved the overall health condition 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 the survival time. This might provide novel options for treating musculoskeletal complications in breast cancer patients. .",
keywords = "Adaptor Proteins, Signal Transducing/drug effects, Animals, Antineoplastic Agents, Immunological/pharmacology, Benzothiazoles, Bone Neoplasms/metabolism, Bone Resorption/prevention & control, Bone and Bones/pathology, Breast Neoplasms/metabolism, Cell Differentiation/drug effects, Cell Line, Tumor, Disease Models, Animal, Female, Mice, Mice, SCID, Muscle Weakness/pathology, NF-kappa B/metabolism, Osteoblasts/metabolism, Osteoclasts, Osteogenesis/drug effects, PAX7 Transcription Factor/metabolism",
author = "Eric Hesse and Saskia Schr{\"o}der and Diana Brandt and Jenny Pamperin and Hiroaki Saito and Hanna Taipaleenm{\"a}ki",
year = "2019",
month = apr,
day = "9",
doi = "10.1172/jci.insight.125543",
language = "English",
volume = "5",
journal = "JCI INSIGHT",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",

}

RIS

TY - JOUR

T1 - Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness

AU - Hesse, Eric

AU - Schröder, Saskia

AU - Brandt, Diana

AU - Pamperin, Jenny

AU - Saito, Hiroaki

AU - Taipaleenmäki, Hanna

PY - 2019/4/9

Y1 - 2019/4/9

N2 - Breast cancer bone metastases often cause a debilitating non-curable condition with osteolytic lesions, muscle weakness and a high mortality. Current treatment comprises chemotherapy, irradiation, surgery and anti-resorptive drugs that restrict but do not revert bone destruction. In metastatic breast cancer cells, we determined 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 metastases without tumor cell dissemination to other distant sites. Sclerostin inhibition prevented the cancer-induced bone destruction by augmenting osteoblast-mediated bone formation and 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 ultimately muscle function. These effects improved the overall health condition 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 the survival time. This might provide novel options for treating musculoskeletal complications in breast cancer patients. .

AB - Breast cancer bone metastases often cause a debilitating non-curable condition with osteolytic lesions, muscle weakness and a high mortality. Current treatment comprises chemotherapy, irradiation, surgery and anti-resorptive drugs that restrict but do not revert bone destruction. In metastatic breast cancer cells, we determined 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 metastases without tumor cell dissemination to other distant sites. Sclerostin inhibition prevented the cancer-induced bone destruction by augmenting osteoblast-mediated bone formation and 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 ultimately muscle function. These effects improved the overall health condition 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 the survival time. This might provide novel options for treating musculoskeletal complications in breast cancer patients. .

KW - Adaptor Proteins, Signal Transducing/drug effects

KW - Animals

KW - Antineoplastic Agents, Immunological/pharmacology

KW - Benzothiazoles

KW - Bone Neoplasms/metabolism

KW - Bone Resorption/prevention & control

KW - Bone and Bones/pathology

KW - Breast Neoplasms/metabolism

KW - Cell Differentiation/drug effects

KW - Cell Line, Tumor

KW - Disease Models, Animal

KW - Female

KW - Mice

KW - Mice, SCID

KW - Muscle Weakness/pathology

KW - NF-kappa B/metabolism

KW - Osteoblasts/metabolism

KW - Osteoclasts

KW - Osteogenesis/drug effects

KW - PAX7 Transcription Factor/metabolism

U2 - 10.1172/jci.insight.125543

DO - 10.1172/jci.insight.125543

M3 - SCORING: Journal article

C2 - 30965315

VL - 5

JO - JCI INSIGHT

JF - JCI INSIGHT

SN - 2379-3708

ER -