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¹ Department of Endocrinology, Leiden University Medical Center, 2333 ZA Leiden, Netherlands
² Division of Cellular Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands
³ Department of Otolaryngology, Weltevreden Park 1715, South Africa

Address correspondence to R.L. van Bezooijen, Dept. of Endocrinology, C4-R, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands. Phone: 31-71-5263076; Fax: 31-71-5248136; email: R.L.van_Bezooyen{at}lumc.nl

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.

Key Words: sclerosteosis • SOST • osteoblast • Smad phosphorylation • MSC

Abbreviations used in this paper: ALP, alkaline phosphatase; BMP, bone morphogenetic protein; BRE, BMP response element; CoM, control medium; MSC, mesenchymal stromal cell; PTHrP, parathyroid hormone-related protein; SF9, Spodoptera frugiperda.

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