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      About Blood Purification: 3.0 Impact Factor I 5.6 CiteScore I 0.83 Scimago Journal & Country Rank (SJR)

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      Sclerostin Declines during Hemodialysis and Appears in Dialysate

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          Abstract

          Background/Aims: Sclerostin, a soluble inhibitor of Wnt-signaling, inhibits bone formation. We assessed the impact of dialysis on serum sclerostin and whether sclerostin is detectable in effluent dialysates. Methods: In a prospective study of 54 prevalent hemodialysis patients, parameters of bone and mineral metabolism were assessed at the beginning and at the end of dialysis. In a subset of patients (n = 19) sclerostin was measured in serum at start, 1, 2, and 3 h of dialysis and in the effluent dialysate at several points in time. Results: Sclerostin serum levels decreased from median 71.4 pmol/l to 43.5 pmol/l during dialysis (p < 0.0001). In patients with high pre-dialysis sclerostin serum levels, sclerostin was detected in the dialysate. Higher Kt/V correlated with greater relative decrease of sclerostin ( r = 0.467; p = 0.001). Conclusion: Sclerostin is dialysable. Furthermore, sclerostin serum levels decrease during dialysis. Whether targeting lower sclerostin levels by means of improved dialysis adequacy has direct relevance to bone disease remains to be shown.

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          Regulation of bone mass by Wnt signaling.

          Venkatesh Krishnan, Henry Bryant, Ormond A Macdougald (2006)
          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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            Sclerostin Is an Osteocyte-expressed Negative Regulator of Bone Formation, But Not a Classical BMP Antagonist

            Rutger L van Bezooijen, Bernard A.J. Roelen, Annemieke Visser … (2004)
            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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              Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody.

              Desmond Padhi, Graham Jang, Brian Stouch … (2011)
              Sclerostin, an osteocyte-secreted protein, negatively regulates osteoblasts and inhibits bone formation. In this first-in-human study, a sclerostin monoclonal antibody (AMG 785) was administered to healthy men and postmenopausal women. In this phase I, randomized, double-blind, placebo-controlled, ascending, single-dose study, 72 healthy subjects received AMG 785 or placebo (3:1) subcutaneously (0.1, 0.3, 1, 3, 5, or 10 mg/kg) or intravenously (1 or 5 mg/kg). Depending on dose, subjects were followed for up to 85 days. The effects of AMG 785 on safety and tolerability (primary objectives) and pharmacokinetics, bone turnover markers, and bone mineral density (secondary objectives) were evaluated. AMG 785 generally was well tolerated. One treatment-related serious adverse event of nonspecific hepatitis was reported and was resolved. No deaths or study discontinuations occurred. AMG 785 pharmacokinetics were nonlinear with dose. Dose-related increases in the bone-formation markers procollagen type 1 N-propeptide (P1NP), bone-specific alkaline phosphatase (BAP), and osteocalcin were observed, along with a dose-related decrease in the bone-resorption marker serum C-telopeptide (sCTx), resulting in a large anabolic window. In addition, statistically significant increases in bone mineral density of up to 5.3% at the lumbar spine and 2.8% at the total hip compared with placebo were observed on day 85. Six subjects in the higher-dose groups developed anti-AMG 785 antibodies, 2 of which were neutralizing, with no discernible effect on the pharmacokinetics or pharmacodynamics. In summary, single doses of AMG 785 generally were well tolerated, and the data support further clinical investigation of sclerostin inhibition as a potential therapeutic strategy for conditions that could benefit from increased bone formation. © 2011 American Society for Bone and Mineral Research.
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                Author and article information

                Journal
                Journal ID (publisher-id): BPU
                Journal ID (nlm-ta): Blood Purif
                Journal ID (doi): 10.1159/issn.0253-5068
                Title: Blood Purification
                Publisher: S. Karger AG
                ISSN (Print): 0253-5068
                ISSN (Electronic): 1421-9735
                Publication date Subscription-year: 2014
                Publication date (Print): November 2014
                Publication date (Electronic): 13 September 2014
                Volume: 38
                Issue: 1
                Pages: 30-36
                Affiliations
                aDivision of Nephrology and Dialysis, Department of Medicine III and bDepartment of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
                Author notes
                *Daniel Cejka, MD, Medical University of Vienna, Division of Nephrology and Dialysis, Währinger Gürtel 18-20, AT-1090 Vienna (Austria), E-Mail daniel.cejka@meduniwien.ac.at
                Article
                Publisher ID: 364992 Other ID: Blood Purif 2014;38:30-36
                DOI: 10.1159/000364992
                PubMed ID: 25228355
                SO-VID: e02a7480-5814-4a9e-a3f0-65b23b9d6fd0
                Copyright © © 2014 S. Karger AG, Basel
                License:

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Date received : 09 August 2013
                Date accepted : 03 June 2014
                Page count
                Figures: 9, Tables: 2, Pages: 7
                Categories
                Subject: Original Paper

                ScienceOpen disciplines: Cardiovascular Medicine,Nephrology
                Keywords: Kidney failure, chronic,Dialysis solutions,Hyperparathyroidism secondary,Sclerostin protein, human,Parathyroid hormone,Renal dialysis
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine, Nephrology
                Keywords: Kidney failure, chronic, Dialysis solutions, Hyperparathyroidism secondary, Sclerostin protein, human, Parathyroid hormone, Renal dialysis

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