Sclerostin Is an Osteocyte-expressed Negative Regulator of Bone Formation, But Not a Classical BMP Antagonist
By R. van Bezooijen, B. Roelen, A. Visser, L. van der Wee‐Pals, Edwin de Wilt, M. Karperien, H. Hamersma, S. Papapoulos, P. ten Dijke, C. Löwik. Journal of Experimental Medicine, 2004
900 citations recorded by the source corpus.
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.
Subfields: Molecular Biology, Orthopedics and Sports Medicine
View Paper: https://www.semanticscholar.org/paper/61e39a19a1d8a078236c0d02d9b79d2698accf8a
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Citations in the corpus
- The Amazing Osteocyte (2010, background): “Sclerostin was thought to be a bone morphogenetic protein (BMP) antagonist but later was discovered to be involved in the Wnt pathway as an antagonist against lipoprotein receptor 5 (LRP5), a positive regulator of bone mass.((48,49)) Mechanical loading also has been reported to reduce sclerostin exp”
- SOST is a target gene for PTH in bone. (2005, background): “Recently, the SOST gene and its protein product sclerostin were identified as a novel potent negative regulator of bone formation [27,28].”
- Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. (2007, background): “It is possible that Wnt signaling is not completely lost in LRP5 null mice because they still express LRP6, which can also be activated by Wnts.”
- Sclerostin Mediates Bone Response to Mechanical Unloading Through Antagonizing Wnt/β‐Catenin Signaling (2009, background): “(20) In addition, sclerostin protein expression was relatively restricted in bone postnatally, unlike Lrp5.”