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      Osteocytic osteolysis: time for a second look?

      review-article
      a , 1
      BoneKEy Reports
      Nature Publishing Group

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          Abstract

          Over 100 years ago it was suggested that osteocytes could remodel their surrounding environment by removing and replacing bone. In the 1960s and 1970s, many observations were made to suggest that osteocytes could resorb bone and increase the size of their lacunae. This concept became known as osteocytic osteolysis and studies suggested that it occurred in response to diverse stimuli such as parathyroid hormone, calcium restriction, hibernation and reproductive cycles. However, this concept fell out of favor in the late 1970s when it became clear that osteoclasts were the principal bone-resorbing cells in the skeleton. Over the past decade, we have increasingly appreciated that osteocytes are remarkably versatile cells and are involved in all aspects of skeletal biology, including the response to loading, the regulation of bone turnover and the control of mineral metabolism. Recent data have demonstrated that osteocytes remodel their perilacunar and canalicular matrix and participate in the liberation of skeletal calcium stores during lactation. In light of these new findings, it may be time to reassess the concept of osteocytic osteolysis and reconsider whether osteocyte lacunar and canalicular remodeling contributes more broadly to the maintenance of skeletal and mineral homeostasis.

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          Most cited references49

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          Sclerostin Is an Osteocyte-expressed Negative Regulator of Bone Formation, But Not a Classical BMP Antagonist

          Sclerosteosis, a skeletal disorder characterized by high bone mass due to increased osteoblast activity, is caused by loss of the SOST gene product, sclerostin. The localization in bone and the mechanism of action of sclerostin are not yet known, but it has been hypothesized that it may act as a bone morphogenetic protein (BMP) antagonist. We show here that SOST/sclerostin is expressed exclusively by osteocytes in mouse and human bone and inhibits the differentiation and mineralization of murine preosteoblastic cells (KS483). Although sclerostin shares some of the actions of the BMP antagonist noggin, we show here that it also has actions distinctly different from it. In contrast to noggin, sclerostin did not inhibit basal alkaline phosphatase (ALP) activity in KS483 cells, nor did it antagonize BMP-stimulated ALP activity in mouse C2C12 cells. In addition, sclerostin had no effect on BMP-stimulated Smad phosphorylation and direct transcriptional activation of MSX-2 and BMP response element reporter constructs in KS483 cells. Its unique localization and action on osteoblasts suggest that sclerostin may be the previously proposed osteocyte-derived factor that is transported to osteoblasts at the bone surface and inhibits bone formation.
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            Osteocytes as dynamic multifunctional cells.

            The target of bone systemic factors and therapeutics has been assumed to be primarily osteoblasts and/or osteoclasts and their precursors. All the action with regard to bone modeling or remodeling has been assumed to take place on the bone surface. In this scenario, cells below the bone surface, that is, osteocyte, are considered to be inactive placeholders in the bone matrix. New data show osteocytes are involved. In addition to the function of osteocytes translating mechanical strain into biochemical signals between osteocytes and cells on the bone surface to affect (re)modeling, new functions are emerging. Osteocytes are exquisitely sensitive to mechanical strain in the form of shear stress compared to osteoblasts or osteoclasts and communicate with each other, with cells on the bone surface, and with marrow cells. Osteocytes are able to move their cell body and their dendritic processes and appear to be able to modify their local microenvironment. A novel function now attributed to osteocytes includes regulation of phosphate metabolism. Therefore, in addition to osteoblasts and osteoclasts, osteocytes are also important for bone health.
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              Osteocyte RANKL: new insights into the control of bone remodeling.

              The idea that osteoblasts, or their progenitors, support osteoclast formation by expressing the cytokine receptor activator of NFkB ligand (RANKL) is a widely held tenet of skeletal biology. Two recent studies provide evidence that osteocytes, and not osteoblasts or their progenitors, are the major source of RANKL driving osteoclast formation in cancellous bone. The goal of this review is to highlight the results of these new studies and discuss their implications for our understanding of bone remodeling. Copyright © 2012 American Society for Bone and Mineral Research.
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                Author and article information

                Journal
                Bonekey Rep
                Bonekey Rep
                BoneKEy Reports
                Nature Publishing Group
                2047-6396
                2012
                05 December 2012
                : 1
                : 229
                Affiliations
                [1 ]Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine , New Haven, CT, USA
                Author notes
                [a ]Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine , TAC S131, New Haven, CT 06520 8020, USA. Email: john.wysolmerski@ 123456yale.edu
                Article
                bonekey2012229
                10.1038/bonekey.2012.229
                3868715
                24363929
                cd070638-1e95-4a62-9076-cba59791514f
                Copyright © 2012, International Bone & Mineral Society

                This work is licensed under a Creative Commons Attribution 3.0 Unported License License. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/ http://creativecommons.org/licenses/by/3.0/

                History
                : 02 August 2012
                : 18 October 2012
                : 29 October 2012
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