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      Human mesenchymal stem cells as delivery of osteoprotegerin gene: homing and therapeutic effect for osteosarcoma

      , , , ,

      Drug Design, Development and Therapy

      Dove Medical Press

      therapy, MSC, OPG, bone tumor

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          Abstract

          Biological treatments have been studied extensively and previous studies have proved that osteoprotegerin (OPG) can inhibit the development and progress of human osteosarcoma. However, the utility of biologic agents for cancer therapy has a short half-life, which can hardly deliver to and function in tumor sites efficiently. Mesenchymal stem cells (MSCs) have the potential to migrate to tumor sites. In this study, MSCs transfected with adenoviruses carrying the OPG gene (MSCs-OPG) were used via the tail vein to treat athymic nude mice (nu/nu) bearing osteosarcoma. In vivo and ex vivo images were used to validate the MSCs homing to tumors. The therapeutic effect for osteosarcoma was evaluated by observations on growth of tumors and bone destruction. The results showed that infected MSCs-OPG labeled with red fluorescent protein (RFP) can migrate to tumor sites and express OPG protein. The treatment by MSCs-OPG reduced the tumor growth and inhibited bone destruction in vivo. All these indicated that MSCs can deliver OPG to tumor sites, which could be a new direction of biological treatment for human osteosarcoma.

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          Most cited references 27

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          Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand.

          Bone remodelling and bone loss are controlled by a balance between the tumour necrosis factor family molecule osteoprotegerin ligand (OPGL) and its decoy receptor osteoprotegerin (OPG). In addition, OPGL regulates lymph node organogenesis, lymphocyte development and interactions between T cells and dendritic cells in the immune system. The OPGL receptor, RANK, is expressed on chondrocytes, osteoclast precursors and mature osteoclasts. OPGL expression in T cells is induced by antigen receptor engagement, which suggests that activated T cells may influence bone metabolism through OPGL and RANK. Here we report that activated T cells can directly trigger osteoclastogenesis through OPGL. Systemic activation of T cells in vivo leads to an OPGL-mediated increase in osteoclastogenesis and bone loss. In a T-cell-dependent model of rat adjuvant arthritis characterized by severe joint inflammation, bone and cartilage destruction and crippling, blocking of OPGL through osteoprotegerin treatment at the onset of disease prevents bone and cartilage destruction but not inflammation. These results show that both systemic and local T-cell activation can lead to OPGL production and subsequent bone loss, and they provide a novel paradigm for T cells as regulators of bone physiology.
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            Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas.

            The poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor. Because it has been suggested that circulating bone marrow-derived stem cells can be recruited into solid organs in response to tissue stresses, we hypothesized that human bone marrow-derived mesenchymal stem cells (hMSC) may have a tropism for brain tumors and thus could be used as delivery vehicles for glioma therapy. To test this, we isolated hMSCs from bone marrow of normal volunteers, fluorescently labeled the cells, and injected them into the carotid artery of mice bearing human glioma intracranial xenografts (U87, U251, and LN229). hMSCs were seen exclusively within the brain tumors regardless of whether the cells were injected into the ipsilateral or contralateral carotid artery. In contrast, intracarotid injections of fibroblasts or U87 glioma cells resulted in widespread distribution of delivered cells without tumor specificity. To assess the potential of hMSCs to track human gliomas, we injected hMSCs directly into the cerebral hemisphere opposite an established human glioma and showed that the hMSCs were capable of migrating into the xenograft in vivo. Likewise, in vitro Matrigel invasion assays showed that conditioned medium from gliomas, but not from fibroblasts or astrocytes, supported the migration of hMSCs and that platelet-derived growth factor, epidermal growth factor, or stromal cell-derived factor-1alpha, but not basic fibroblast growth factor or vascular endothelial growth factor, enhanced hMSC migration. To test the potential of hMSCs to deliver a therapeutic agent, hMSCs were engineered to release IFN-beta (hMSC-IFN-beta). In vitro coculture and Transwell experiments showed the efficacy of hMSC-IFN-beta against human gliomas. In vivo experiments showed that treatment of human U87 intracranial glioma xenografts with hMSC-IFN-beta significantly increase animal survival compared with controls (P < 0.05). We conclude that hMSCs can integrate into human gliomas after intravascular or local delivery, that this engraftment may be mediated by growth factors, and that this tropism of hMSCs for human gliomas can be exploited to therapeutic advantage.
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              Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors.

              Molecules that physiologically control cell proliferation are often produced locally in tissues and are rapidly destroyed when they enter circulation. This allows local effects while avoiding interference with other systems. Unfortunately, it also limits the therapeutic use of these molecules via systemic delivery. We here demonstrate that, for the purpose of anticancer therapy, bone marrow-derived mesenchymal stem cells (MSCs) can produce biological agents locally at tumor sites. We show that the tumor microenvironment preferentially promotes the engraftment of MSCs as compared with other tissues. MSCs with forced expression of IFN-beta inhibited the growth of malignant cells in vivo. Importantly, this effect required the integration of MSCs into the tumors and could not be achieved by systemically delivered IFN-beta or by IFN-beta produced by MSCs at a site distant from the tumors. Our results indicate that MSCs may serve as a platform for delivery of biological agents in tumors.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                17 February 2015
                : 9
                : 969-976
                Affiliations
                Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
                Author notes
                Correspondence: Shuquan Guo, Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, People’s Republic of China, Tel +86 23 8901 1202, Fax +86 23 8901 1217, Email 514629902@ 123456qq.com
                Article
                dddt-9-969
                10.2147/DDDT.S77116
                4338779
                © 2015 Qiao et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                therapy, msc, opg, bone tumor

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