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      Bisphosphonate Treatment Ameliorates Chemotherapy-Induced Bone and Muscle Abnormalities in Young Mice

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          Abstract

          Chemotherapy is frequently accompanied by several side effects, including nausea, diarrhea, anorexia and fatigue. Evidence from ours and other groups suggests that chemotherapy can also play a major role in causing not only cachexia, but also bone loss. This complicates prognosis and survival among cancer patients, affects quality of life, and can increase morbidity and mortality rates. Recent findings suggest that soluble factors released from resorbing bone directly contribute to loss of muscle mass and function secondary to metastatic cancer. However, it remains unknown whether similar mechanisms also take place following treatments with anticancer drugs. In this study, we found that young male CD2F1 mice (8-week old) treated with the chemotherapeutic agent cisplatin (2.5 mg/kg) presented marked loss of muscle and bone mass. Myotubes exposed to bone conditioned medium from cisplatin-treated mice showed severe atrophy (−33%) suggesting a bone to muscle crosstalk. To test this hypothesis, mice were administered cisplatin in combination with an antiresorptive drug to determine if preservation of bone mass has an effect on muscle mass and strength following chemotherapy treatment. Mice received cisplatin alone or combined with zoledronic acid (ZA; 5 μg/kg), a bisphosphonate routinely used for the treatment of osteoporosis. We found that cisplatin resulted in progressive loss of body weight (−25%), in line with reduced fat (−58%) and lean (−17%) mass. As expected, microCT bone histomorphometry analysis revealed significant reduction in bone mass following administration of chemotherapy, in line with reduced trabecular bone volume (BV/TV) and number (Tb.N), as well as increased trabecular separation (Tb.Sp) in the distal femur. Conversely, trabecular bone was protected when cisplatin was administered in combination with ZA. Interestingly, while the animals exposed to chemotherapy presented significant muscle wasting (~-20% vs. vehicle-treated mice), the administration of ZA in combination with cisplatin resulted in preservation of muscle mass (+12%) and strength (+42%). Altogether, these observations support our hypothesis of bone factors targeting muscle and suggest that pharmacological preservation of bone mass can benefit muscle mass and function following chemotherapy.

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          Most cited references 85

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          Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit.

           T. Martin,  N Sims (2014)
          Coupling between bone formation and bone resorption refers to the process within basic multicellular units in which resorption by osteoclasts is met by the generation of osteoblasts from precursors, and their bone-forming activity, which needs to be sufficient to replace the bone lost. There are many sources of activities that contribute to coupling at remodeling sites, including growth factors released from the matrix, soluble and membrane products of osteoclasts and their precursors, signals from osteocytes and from immune cells and signaling taking place within the osteoblast lineage. Coupling is therefore a process that involves the interaction of a wide range of cell types and control mechanisms. As bone remodeling occurs at many sites asynchronously throughout the skeleton, locally generated activities comprise very important control mechanisms. In this review, we explore the potential roles of a number of these factors, including sphingosine-1-phosphate, semaphorins, ephrins, interleukin-6 (IL-6) family cytokines and marrow-derived factors. Their interactions achieve the essential tight control of coupling within individual remodeling units that is required for control of skeletal mass.
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            The contribution of bone to whole-organism physiology.

            The mouse genetic revolution has shown repeatedly that most organs have more functions than expected. This has led to the realization that, in addition to a molecular and cellular approach, there is a need for a whole-organism study of physiology. The skeleton is an example of how a whole-organism approach to physiology can broaden the functions of a given organ, reveal connections of this organ with others such as the brain, pancreas and gut, and shed new light on the pathogenesis of degenerative diseases affecting multiple organs.
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              Excess TGF-β mediates muscle weakness associated with bone metastases in mice

              Cancer-associated muscle weakness is poorly understood 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 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/calcium (Ca2+) release channel (RyR1). The oxidized RyR1 channels leaked Ca2+, resulting in lower intracellular signaling required for proper muscle contraction. We found that inhibiting RyR1 leak, TGF-β signaling, TGF-β release from bone or Nox4 all improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast cancer- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, higher levels of Nox4 protein and Nox4 binding to RyR1, and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a non-malignant metabolic bone disorder associated with increased TGF-β activity. Thus, metastasis-induced TGF-β release from bone contributes to muscle weakness by decreasing Ca2+-induced muscle force production.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                19 November 2019
                2019
                : 10
                Affiliations
                1Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine , Indianapolis, IN, United States
                2Department of Surgery, Indiana University School of Medicine , Indianapolis, IN, United States
                3Indiana Center for Musculoskeletal Health, Indiana University School of Medicine , Indianapolis, IN, United States
                4Simon Comprehensive Cancer Center, Indiana University , Indianapolis, IN, United States
                5Department of Orthopaedic Surgery, Indiana University School of Medicine , Indianapolis, IN, United States
                6IUPUI Center for Cachexia Research, Innovation and Therapy, Indiana University School of Medicine , Indianapolis, IN, United States
                7Department of Otolaryngology – Head & Neck Surgery, Indiana University School of Medicine , Indianapolis, IN, United States
                Author notes

                Edited by: Marco Invernizzi, University of Eastern Piedmont, Italy

                Reviewed by: Jan Josef Stepan, Charles University, Czechia; Natalie A. Sims, St. Vincents Institute of Medical Research, Australia; Michael Gnant, Medical University of Vienna, Austria

                *Correspondence: Andrea Bonetto abonetto@ 123456iu.edu

                This article was submitted to Bone Research, a section of the journal Frontiers in Endocrinology

                †These authors have contributed equally to this work

                Article
                10.3389/fendo.2019.00809
                6877551
                Copyright © 2019 Essex, Pin, Huot, Bonewald, Plotkin and Bonetto.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 11, Tables: 0, Equations: 0, References: 107, Pages: 15, Words: 10918
                Funding
                Funded by: American Cancer Society 10.13039/100000048
                Award ID: 132013-RSG-18-010-01-CCG
                Funded by: V Foundation for Cancer Research 10.13039/100001368
                Funded by: Ralph W. and Grace M. Showalter Research Trust Fund 10.13039/100007114
                Categories
                Endocrinology
                Original Research

                Endocrinology & Diabetes

                bisphosphonates, muscle, chemotherapy, cachexia, bone

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