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      The Osteoclast in Bone Metastasis: Player and Target

      review-article
      , *
      Cancers
      MDPI
      breast cancer, bone metastases, osteoclasts, antiresorptive drugs, vicious cycle

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          Abstract

          Bone metastases are frequently the final fate of breast and prostate cancer patients. According to the definition of metastasis as an incurable disease, to date there are no effective treatments for tumor-associated bone metastases and this represents a real challenge for the researchers in the field. The bone is a heterogeneous environment that represents a fertile soil for tumor cells, supporting their growth. Among the different cell types present in the bone, in this review we will focus our attention on the osteoclasts, which are crucial players in the so called “vicious cycle”, a phenomenon triggered by tumor cells eventually leading to both tumor proliferation as well as bone deregulation, thus fueling the development of bone metastasis. The complex network, linking tumor cells to the bone by activating osteoclasts, represents a fruitful target for the treatment of bone metastases. In this review we will describe how tumor cells perturb the bone microenvironment by actively influencing osteoclast formation and activity. Moreover, we will describe the current antiresorptive drugs employed in the treatment of bone metastases as well as new, targeted therapies able to affect both cancer cells and osteoclasts.

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          Most cited references89

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          WNT signaling in bone homeostasis and disease: from human mutations to treatments.

          Low bone mass and strength lead to fragility fractures, for example, in elderly individuals affected by osteoporosis or children with osteogenesis imperfecta. A decade ago, rare human mutations affecting bone negatively (osteoporosis-pseudoglioma syndrome) or positively (high-bone mass phenotype, sclerosteosis and Van Buchem disease) have been identified and found to all reside in components of the canonical WNT signaling machinery. Mouse genetics confirmed the importance of canonical Wnt signaling in the regulation of bone homeostasis, with activation of the pathway leading to increased, and inhibition leading to decreased, bone mass and strength. The importance of WNT signaling for bone has also been highlighted since then in the general population in numerous genome-wide association studies. The pathway is now the target for therapeutic intervention to restore bone strength in millions of patients at risk for fracture. This paper reviews our current understanding of the mechanisms by which WNT signalng regulates bone homeostasis.
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            Romosozumab in postmenopausal women with low bone mineral density.

            Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation.
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              Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts.

              Estrogen prevents osteoporotic bone loss by attenuating bone resorption; however, the molecular basis for this is unknown. Here, we report a critical role for the osteoclastic estrogen receptor alpha (ERalpha) in mediating estrogen-dependent bone maintenance in female mice. We selectively ablated ERalpha in differentiated osteoclasts (ERalpha(DeltaOc/DeltaOc)) and found that ERalpha(DeltaOc/DeltaOc) females, but not males, exhibited trabecular bone loss, similar to the osteoporotic bone phenotype in postmenopausal women. Further, we show that estrogen induced apoptosis and upregulation of Fas ligand (FasL) expression in osteoclasts of the trabecular bones of WT but not ERalpha(DeltaOc/DeltaOc) mice. The expression of ERalpha was also required for the induction of apoptosis by tamoxifen and estrogen in cultured osteoclasts. Our results support a model in which estrogen regulates the life span of mature osteoclasts via the induction of the Fas/FasL system, thereby providing an explanation for the osteoprotective function of estrogen as well as SERMs.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                27 June 2018
                July 2018
                : 10
                : 7
                : 218
                Affiliations
                Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy; antoniomaurizi@ 123456outlook.com
                Author notes
                [* ]Correspondence: nadia.rucci@ 123456univaq.it ; Tel.: +39-0862-433525; Fax: +39-0862-433523
                Article
                cancers-10-00218
                10.3390/cancers10070218
                6071064
                29954079
                6b120184-b732-4bfd-88ee-44c01b596674
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 01 June 2018
                : 21 June 2018
                Categories
                Review

                breast cancer,bone metastases,osteoclasts,antiresorptive drugs,vicious cycle

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