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      Sclerostin, an emerging therapeutic target for treating osteoporosis and osteoporotic fracture: A general review

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          Summary

          Osteoporosis and its associated fracture risk has become one of the major health burdens in our aging population. Currently, bisphosphonate, one of the most popular antiresorptive drugs, is used widely to treat osteoporosis but so far still no consensus has been reached for its application in treatment of osteoporotic fractures. However, in old patients, boosting new bone formation and its remodelling is essential for bone healing in age-related osteoporosis and osteoporotic fractures. Sclerostin, an inhibitor of the Wnt/β-catenin signalling pathway that regulates bone growth, has become an attractive therapeutic target for treating osteoporosis. In this review, we summarize the recent findings of sclerostin and its potential as an effective drug target for treating both osteoporosis and osteoporotic fractures.

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          Most cited references 111

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          Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis.

          Chondrocytes and osteoblasts are two primary cell types in the skeletal system that are differentiated from common mesenchymal progenitors. It is believed that osteoblast differentiation is controlled by distinct mechanisms in intramembranous and endochondral ossification. We have found that ectopic canonical Wnt signaling leads to enhanced ossification and suppression of chondrocyte formation. Conversely, genetic inactivation of beta-catenin, an essential component transducing the canonical Wnt signaling, causes ectopic formation of chondrocytes at the expense of osteoblast differentiation during both intramembranous and endochondral ossification. Moreover, inactivation of beta-catenin in mesenchymal progenitor cells in vitro causes chondrocyte differentiation under conditions allowing only osteoblasts to form. Our results demonstrate that beta-catenin is essential in determining whether mesenchymal progenitors will become osteoblasts or chondrocytes regardless of regional locations or ossification mechanisms. Controlling Wnt/beta-catenin signaling is a common molecular mechanism underlying chondrocyte and osteoblast differentiation and specification of intramembranous and endochondral ossification.
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            Regulation of bone mass by Wnt signaling.

            Wnt proteins are a family of secreted proteins that regulate many aspects of cell growth, differentiation, function, and death. Considerable progress has been made in our understanding of the molecular links between Wnt signaling and bone development and remodeling since initial reports that mutations in the Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) are causally linked to alterations in human bone mass. Of the pathways activated by Wnts, it is signaling through the canonical (i.e., Wnt/beta-catenin) pathway that increases bone mass through a number of mechanisms including renewal of stem cells, stimulation of preosteoblast replication, induction of osteoblastogenesis, and inhibition of osteoblast and osteocyte apoptosis. This pathway is an enticing target for developing drugs to battle skeletal diseases as Wnt/beta-catenin signaling is composed of a series of molecular interactions that offer potential places for pharmacological intervention. In considering opportunities for anabolic drug discovery in this area, one must consider multiple factors, including (a) the roles of Wnt signaling for development, remodeling, and pathology of bone; (b) how pharmacological interventions that target this pathway may specifically treat osteoporosis and other aspects of skeletal health; and (c) whether the targets within this pathway are amenable to drug intervention. In this Review we discuss the current understanding of this pathway in terms of bone biology and assess whether targeting this pathway might yield novel therapeutics to treat typical bone disorders.
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              Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group.

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                Author and article information

                Contributors
                Journal
                J Orthop Translat
                J Orthop Translat
                Journal of Orthopaedic Translation
                Chinese Speaking Orthopaedic Society
                2214-031X
                2214-0328
                12 September 2015
                January 2016
                12 September 2015
                : 4
                : 1-13
                Affiliations
                [1]Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China
                Author notes
                []Corresponding authors. P.K. Suen, State Key Laboratory of Agrobiotechnology, Room EG02, Science Centre East Block, The Chinese University of Hong Kong, Hong Kong SAR, China; L. Qin, Department of Orthopaedics & Traumatology, 5/F Lui Che Woo Clinical Sciences Building, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China. ericsuen@ 123456hotmail.com in@ 123456ort.cuhk.edu.hk
                [1]

                Current address: State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong SAR, China.

                Article
                S2214-031X(15)00061-3
                10.1016/j.jot.2015.08.004
                5987014
                dd91ba61-bcf4-4642-8f4d-9058eba69f32
                © 2016 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                Categories
                Review Article

                osteoporosis, osteoporotic fracture, sclerostin

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