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      Bone Disease in Multiple Myeloma: Pathophysiology and Management

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          Abstract

          Myeloma bone disease (MBD) is a devastating complication of multiple myeloma (MM). More than 80% of MM patients suffer from destructive bony lesions, leading to pain, fractures, mobility issues, and neurological deficits. MBD is not only a main cause of disability and morbidity in MM patients but also increases the cost of management. Bone destruction and lack of bone formation are main factors in the development of MBD. Some novel factors are found to be involved in the pathogenesis of MBD, eg, receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) system (RANKL/OPG), Wingless (Wnt), dickkopf-1 (Wnt/DKK1) pathway. The addition of novel agents in the treatment of MM, use of bisphosphonates and other supportive modalities such as radiotherapy, vertebroplasty/kyphoplasty, and surgical interventions, all have significant roles in the treatment of MBD. This review provides an overview on the pathophysiology and management of MBD.

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          LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.

          In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.
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            High bone density due to a mutation in LDL-receptor-related protein 5.

            Osteoporosis is a major public health problem of largely unknown cause. Loss-of-function mutations in the gene for low-density lipoprotein receptor-related protein 5 (LRP5), which acts in the Wnt signaling pathway, have been shown to cause osteoporosis-pseudoglioma. We performed genetic and biochemical analyses of a kindred with an autosomal dominant syndrome characterized by high bone density, a wide and deep mandible, and torus palatinus. Genetic analysis revealed linkage of the syndrome to chromosome 11q12-13 (odds of linkage, >1 million to 1), an interval that contains LRP5. Affected members of the kindred had a mutation in this gene, with valine substituted for glycine at codon 171 (LRP5V171). This mutation segregated with the trait in the family and was absent in control subjects. The normal glycine lies in a so-called propeller motif that is highly conserved from fruit flies to humans. Markers of bone resorption were normal in the affected subjects, whereas markers of bone formation such as osteocalcin were markedly elevated. Levels of fibronectin, a known target of signaling by Wnt, a developmental protein, were also elevated. In vitro studies showed that the normal inhibition of Wnt signaling by another protein, Dickkopf-1 (Dkk-1), was defective in the presence of LRP5V171 and that this resulted in increased signaling due to unopposed Wnt activity. The LRP5V171 mutation causes high bone density, with a thickened mandible and torus palatinus, by impairing the action of a normal antagonist of the Wnt pathway and thus increasing Wnt signaling. These findings demonstrate the role of altered LRP5 function in high bone mass and point to Dkk as a potential target for the prevention or treatment of osteoporosis.
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              Developmental stage and time dictate the fate of Wnt/β-catenin-responsive stem cells in the mammary gland.

              The mammary epithelium undergoes extensive growth and remodeling during pregnancy, suggesting a role for stem cells. Yet their origin, identity, and behavior in the intact tissue remain unknown. Using an Axin2(CreERT2) allele, we labeled and traced Wnt/β-catenin-responsive cells throughout mammary gland development. This reveals a switch in Wnt/β-catenin signaling around birth and shows that, depending on the developmental stage, Axin2(+) cells contribute differently to basal and luminal epithelial cell lineages of the mammary epithelium. Moreover, an important difference exists between the developmental potential tested in transplantation assays and that displayed by the same cell population in situ. Finally, Axin2(+) cells in the adult build alveolar structures during multiple pregnancies, demonstrating the existence of a Wnt/β-catenin-responsive adult stem cell. Our study uncovers dynamic changes in Wnt/β-catenin signaling in the mammary epithelium and offers insights into the developmental fate of mammary gland stem and progenitor cells. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Cancer Growth Metastasis
                Cancer Growth Metastasis
                Cancer Growth and Metastasis
                Cancer Growth and Metastasis
                Libertas Academica
                1179-0644
                2014
                10 August 2014
                : 7
                : 33-42
                Affiliations
                [1 ]Medical Oncology Department, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan.
                [2 ]Mater Misericordaie University Hospital, Dublin, Ireland.
                [3 ]Dublin City University, Dublin, Ireland.
                [4 ]Department of Biochemistry, Mater Misericordaie University Hospital, Dublin, Ireland.
                [5 ]National Institute for cellular Biotechnology, Dublin City University, Dublin, Ireland.
                [6 ]Hematology Department, Mater Misericordaie University Hospital, Dublin, Ireland.
                Author notes
                Article
                cgm-7-2014-033
                10.4137/CGM.S16817
                4133035
                25187738
                cbe1ddf2-7148-477b-940e-4a287e08a843
                © 2014 the author(s), publisher and licensee Libertas Academica Ltd.

                This is an open access article published under the Creative Commons CC-BY-NC 3.0 License.

                History
                : 11 May 2014
                : 18 June 2014
                : 20 June 2014
                Categories
                Review

                osteoclasts,osteoclastogenesis,osteoblasts,osteoblastogenesis,cytokines,bisphosphonates

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