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      Clinical and Biological Determinants of Sclerostin Plasma Concentration in Hemodialysis Patients

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          Background: Sclerostin is a potent inhibitor of bone formation, but the meaning of its serum levels remains undetermined. We evaluated the association between sclerostin levels and clinical or biological data in hemodialyzed patients (HD), notably parathormone (PTH), biomarkers of bone turnover, vascular calcifications and mortality after 2 years. Methods: 164 HD patients were included in this observational study. The calcification score was assessed with the Kauppila method. Patients were followed for 2 years. Results: Median sclerostin levels were significantly (p < 0.0001) higher in HD versus healthy subjects (n = 94) (1,375 vs. 565 pg/ml, respectively). In univariate analysis a significant association (p < 0.05) was found between sclerostin and age, height, dialysis vintage, albumin, troponin, homocysteine, PTH, C-terminal telopeptide of collagen type I, bone-specific alkaline phosphatase and osteoprotegerin, but not with the calcification score. In a multivariate model, the association remained with age, height, dialysis vintage, troponin, homocysteine, phosphate, PTH, but also with vascular calcifications. Association was positive for all variables, except PTH and vascular calcifications. The baseline sclerostin concentration was not different in survivors and non-survivors. Conclusions: We confirm a higher concentration of sclerostin in HD patients, a positive association with age and a negative association with PTH. A positive association with phosphate, homocysteine and troponin calls for additional research. The clinical interest of sclerostin to assess vascular calcifications in HD is limited and no association was found between sclerostin and mortality.

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          Most cited references 39

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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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            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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              Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST).

              Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance. Radiologically, it is characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened and sclerotic skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients. By linkage analysis in one extended van Buchem family and two consanguineous sclerosteosis families we previously mapped both disease genes to the same chromosomal 17q12-q21 region, supporting the hypothesis that both conditions are caused by mutations in the same gene. After reducing the disease critical region to approximately 1 Mb, we used the positional cloning strategy to identify the SOST gene, which is mutated in sclerosteosis patients. This new gene encodes a protein with a signal peptide for secretion and a cysteine-knot motif. Two nonsense mutations and one splice site mutation were identified in sclerosteosis patients, but no mutations were found in a fourth sclerosteosis patient nor in the patients from the van Buchem family. As the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation. Therefore, this gene might become an important tool in the development of therapeutic strategies for osteoporosis.

                Author and article information

                Nephron Clin Pract
                Nephron Clinical Practice
                S. Karger AG
                December 2014
                04 November 2014
                : 128
                : 1-2
                : 127-134
                aNephrology-Dialysis-Transplantation and bClinical Chemistry, University of Liège, CHU Sart Tilman, cNephrology-Dialysis and dRadiology, Centre Hospitalier Régional ‘La Citadelle', and eDepartment of Public Health, Epidemiology and Health Economics, University of Liège, Liège, fNephrology-Dialysis, Centre Hospitalier ‘Bois de l'Abbaye', Seraing, and gDepartment of Public Health and Primary Care @ Kulak, University of Leuven, Kulak, Kortrijk, Belgium
                Author notes
                *Pierre Delanaye, Service de Dialyse, CHU Sart Tilman, BE-4000 Liège (Belgium), E-Mail pierre_delanaye@yahoo.fr
                366449 Nephron Clin Pract 2014;128:127-134
                © 2014 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 3, Pages: 8
                Original Paper

                Cardiovascular Medicine, Nephrology

                Sclerostin, Vascular calcification, Bone turnover


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