ArticleNature medicine2015
Excess TGF-β mediates muscle weakness associated with bone metastases in mice.
Article in Nature medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 254 papers, 2 of them syntheses that pooled it.
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The trial behind it
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Who cites it
254 citing papers in PubMed, 2 syntheses or guidelines pooled it, 369 citations in OpenAlex.
- Cancer- and cardiac-induced cachexia: same fate through different inflammatory mediators?Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2022Pooled it
- Comprehensive analysis of multi Ewing sarcoma microarray datasets identifies several prognosis biomarkers.Molecular medicine reports · 2018Pooled it
- Effect of Zoledronic Acid on Skeletal Muscle After Bariatric Surgery: A Secondary Analysis From a Randomized Controlled Trial.Obesity (Silver Spring, Md.) · 2026Trial
- The Association of Bone Turnover Markers with Muscle Function, Falls, and Frailty in Older Women in Long-Term Care.The Journal of frailty & aging · 2023Trial
- Trial
- Trial
- Metastatic Bone Disease Is Associated With Longitudinal Muscle Loss and Reduced Survival in Kidney Cancer.Journal of cachexia, sarcopenia and muscle · 2026Article
- Tumor-Secreted ADAMTSL4 Activates Latent TGFβ1 to Drive Cancer Cachexia.Cancer discovery · 2026Article
- Age-dependent musculoskeletal changes during mechanical unloading with bisphosphonate treatment.Bone · 2026Article
- Targeting TGF-β to Attenuate Ischemia-Reperfusion Associated Muscle Fibrosis and Enhance Regeneration: A Preclinical Study.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Inflammatory neuropathy in mouse and primate models of colorectal cancer.Nature communications · 2026Article
- Myeloid cell reprogramming combined with zoledronic acid effectively suppresses bone metastasis.Cancer biology & medicine · 2026Article
- Understanding cachexia and muscle dysfunction in the context of metastatic breast cancer.Cancer metastasis reviews · 2026Review
- Mechanotransduction Failure and Molecular Rescue in Gastric Cancer: Kinetotherapy Across the IL-6/STAT3-Myostatin/ACVR2B-Akt/mTOR Axis.Medical sciences (Basel, Switzerland) · 2026Review
- ASCL2-mediated macrophage-myofibroblast transition generates immunosuppressive CAF_7 in NSCLC bone metastases.Journal of experimental & clinical cancer research : CR · 2026Article
- Low intensity vibration with zoledronate reduces musculoskeletal weakness and adiposity in estrogen deprived female mice.Nature communications · 2026Article
- Cancer cachexia: molecular basis and therapeutic advances.Signal transduction and targeted therapy · 2026Review
- Exercise-responsive crosstalk within local muscle-bone units in osteosarcopenia: from mechanotransduction to secretome signalling.Frontiers in physiology · 2026Review
- Exploring osteosarcopenia from the gut microbiota perspective: mechanistic insights and therapeutic potentials based on the gut-muscle-bone Axis.Frontiers in microbiology · 2026Review
- Review
194 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
23 authors at 6 institutions in 3 countries.
Funding
Abstract
Cancer-associated muscle weakness is a poorly understood phenomenon, and there is no effective treatment. Here we find that seven different mouse models of human osteolytic bone metastases-representing breast, lung and prostate cancers, as well as multiple myeloma-exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancer-associated muscle weakness. We found that transforming growth factor (TGF)-β, released from the bone surface as a result of metastasis-induced bone destruction, upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor and calcium (Ca(2+)) release channel (RyR1). The oxidized RyR1 channels leaked Ca(2+), resulting in lower intracellular signaling, which is required for proper muscle contraction. We found that inhibiting RyR1 leakage, TGF-β signaling, TGF-β release from bone or Nox4 activity improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, increased Nox4 binding to RyR1 and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a nonmalignant metabolic bone disorder associated with increased TGF-β activity. Thus, pathological TGF-β release from bone contributes to muscle weakness by decreasing Ca(2+)-induced muscle force production.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.