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      Key Triggers of Osteoclast-Related Diseases and Available Strategies for Targeted Therapies: A Review

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          Abstract

          Osteoclasts, the only cells with bone resorption functions in vivo, maintain the balance of bone metabolism by cooperating with osteoblasts, which are responsible for bone formation. Excessive activity of osteoclasts causes many diseases such as osteoporosis, periprosthetic osteolysis, bone tumors, and Paget’s disease. In contrast, osteopetrosis results from osteoclast deficiency. Available strategies for combating over-activated osteoclasts and the subsequently induced diseases can be categorized into three approaches: facilitating osteoclast apoptosis, inhibiting osteoclastogenesis, and impairing bone resorption. Bisphosphonates are representative molecules that function by triggering osteoclast apoptosis. New drugs, such as tumor necrosis factor and receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors (e.g., denosumab) have been developed for targeting the receptor activator of nuclear factor kappa-B /RANKL/osteoprotegerin system or CSF-1/CSF-1R axis, which play critical roles in osteoclast formation. Furthermore, vacuolar (H +)-ATPase inhibitors, cathepsin K inhibitors, and glucagon-like peptide 2 impair different stages of the bone resorption process. Recently, significant achievements have been made in this field. The aim of this review is to provide an updated summary of the current progress in research involving osteoclast-related diseases and of the development of targeted inhibitors of osteoclast formation.

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          Osteoporosis: now and the future.

          Osteoporosis is a common disease characterised by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. With an ageing population, the medical and socioeconomic effect of osteoporosis, particularly postmenopausal osteoporosis, will increase further. A detailed knowledge of bone biology with molecular insights into the communication between bone-forming osteoblasts and bone-resorbing osteoclasts and the orchestrating signalling network has led to the identification of novel therapeutic targets. Novel treatment strategies have been developed that aim to inhibit excessive bone resorption and increase bone formation. The most promising novel treatments include: denosumab, a monoclonal antibody for receptor activator of NF-κB ligand, a key osteoclast cytokine; odanacatib, a specific inhibitor of the osteoclast protease cathepsin K; and antibodies against the proteins sclerostin and dickkopf-1, two endogenous inhibitors of bone formation. This overview discusses these novel therapies and explains their underlying physiology. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Pathogenesis of osteoporosis: concepts, conflicts, and prospects.

            Osteoporosis is a disorder in which loss of bone strength leads to fragility fractures. This review examines the fundamental pathogenetic mechanisms underlying this disorder, which include: (a) failure to achieve a skeleton of optimal strength during growth and development; (b) excessive bone resorption resulting in loss of bone mass and disruption of architecture; and (c) failure to replace lost bone due to defects in bone formation. Estrogen deficiency is known to play a critical role in the development of osteoporosis, while calcium and vitamin D deficiencies and secondary hyperparathyroidism also contribute. There are multiple mechanisms underlying the regulation of bone remodeling, and these involve not only the osteoblastic and osteoclastic cell lineages but also other marrow cells, in addition to the interaction of systemic hormones, local cytokines, growth factors, and transcription factors. Polymorphisms of a large number of genes have been associated with differences in bone mass and fragility. It is now possible to diagnose osteoporosis, assess fracture risk, and reduce that risk with antiresorptive or other available therapies. However, new and more effective approaches are likely to emerge from a better understanding of the regulators of bone cell function.
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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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                Author and article information

                Contributors
                Journal
                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                2296-858X
                20 December 2017
                2017
                : 4
                : 234
                Affiliations
                [1] 1Department of Orthopaedics, The First Affiliated Hospital of Nanchang University, Artificial Joints Engineering and Technology Research Center of Jiangxi Province , Nanchang, China
                [2] 2Department of Orthopaedics, The People’s Hospital of Changxing County , Huzhou, China
                Author notes

                Edited by: Peter N. Robinson, Jackson Laboratory for Genomic Medicine, United States

                Reviewed by: Carole Guillonneau, INSERM UMR1064 Centre de Recherche en Transplantation et Immunologie, France; Melissa Anne Haendel, Oregon Health and Science University, United States

                *Correspondence: Xuqiang Liu, shliuxuqiang@ 123456163.com ; Min Dai, daimin@ 123456medmail.com.cn

                These authors have contributed equally to this work.

                Specialty section: This article was submitted to Translational Medicine, a section of the journal Frontiers in Medicine

                Article
                10.3389/fmed.2017.00234
                5742334
                29326938
                7d5587f3-7181-4869-9076-8a016a4a2d31
                Copyright © 2017 Bi, Chen, Gao, Yu, Xiao, Zhang, Liu and Dai.

                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) or licensor 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.

                History
                : 27 May 2017
                : 04 December 2017
                Page count
                Figures: 1, Tables: 2, Equations: 0, References: 112, Pages: 10, Words: 8925
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81660365, 81601912
                Categories
                Medicine
                Review

                osteoclast,osteoporosis,periprosthetic osteolysis,rheumatoid arthritis,paget’s bonedisease,osteopetrosis

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