title: Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist.
abstract: 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.
authors.affiliation: Department of Endocrinology, C4-R, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Netherlands. R.L.van_Bezooyen@lumc.nl
authors.forename: Rutger L
authors.initials: RL
authors.lastname: van Bezooijen
authors.forename: Bernard A J
authors.initials: BA
authors.lastname: Roelen
authors.forename: Annemieke
authors.initials: A
authors.lastname: Visser
authors.forename: Lianne
authors.initials: L
authors.lastname: van der Wee-Pals
authors.forename: Edwin
authors.initials: E
authors.lastname: de Wilt
authors.forename: Marcel
authors.initials: M
authors.lastname: Karperien
authors.forename: Herman
authors.initials: H
authors.lastname: Hamersma
authors.forename: Socrates E
authors.initials: SE
authors.lastname: Papapoulos
authors.forename: Peter
authors.initials: P
authors.lastname: ten Dijke
authors.forename: Clemens W G M
authors.initials: CW
authors.lastname: Löwik
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001846:Bone Development / Q000502:physiology*; D001848:Bone Diseases, Developmental / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D005819:Genetic Markers / Q000235:genetics / Q000502:physiology; D006023:Glycoproteins; D018398:Homeodomain Proteins; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins; D008156:Luciferases; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism*; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051785:Smad Proteins; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D006023:Glycoproteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; C084119:MSX2 protein; C422903:SOST protein, human; D051785:Smad Proteins; C486030:Sost protein, mouse; D015534:Trans-Activators; D008156:Luciferases; D000469:Alkaline Phosphatase