Sclerostin Binds to LRP5/6 and Antagonizes Canonical Wnt Signaling*

By Xiaofeng Li, Yazhou Zhang, Heeseog Kang, W. Liu, Peng Liu, Jianghong Zhang, S. Harris, Dianqing Wu. Journal of Biological Chemistry, 2005

1,383 citations recorded by the source corpus.

The loss of the SOST gene product sclerostin leads to sclerosteosis characterized by high bone mass. In this report, we found that sclerostin could antagonize canonical Wnt signaling in human embryonic kidney A293T cells and mouse osteoblastic MC3T3 cells. This sclerostin-mediated antagonism could be reversed by overexpression of Wnt co-receptor low density lipoprotein receptor-related protein (LRP) 5. In addition, we found that sclerostin bound to LRP5 as well as LRP6 and identified the first two YWTD-EGF repeat domains of LRP5 as being responsible for the binding. Although these two repeat domains are required for transduction of canonical Wnt signals, canonical Wnt did not appear to compete with sclerostin for binding to LRP5. Examination of the expression of sclerostin and Wnt7b, an autocrine canonical Wnt, during primary calvarial osteoblast differentiation revealed that sclerostin is expressed at late stages of osteoblast differentiation coinciding with the expression of osteogenic marker osteocalcin and trailing after the expression of Wnt7b. Given the plethora of evidence indicating that canonical Wnt signaling stimulates osteogenesis, we believe that the high bone mass phenotype associated with the loss of sclerostin may be attributed, at least in part, to an increase in canonical Wnt signaling resulting from the reduction in sclerostin-mediated Wnt antagonism.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9d411cd5f65daa77f1eed7e572e1a7ec57ea31c8

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Citations in the corpus

Wnt/beta-catenin signaling in development and disease. (2006, positive): “Two groups recently demonstrated that SOST/Sclerostin is a secreted Wnt inhibitor, which binds and blocks LRP5/6 (Li et al., 2005; Semenov et al., 2005).”
Building strong bones: molecular regulation of the osteoblast lineage (2011, background): “Sclerostin seems to function mainly by inhibiting WNT signalling in osteoblast lineage cells, which promotes osteoblast differentiation (see below), but inhibition of bone morphogenetic protein (BMP) signalling has also been suggeste”
Osteocytes, mechanosensing and Wnt signaling. (2008, background): “Regulation of the Wnt/β-catenin signaling pathway is vested largely in proteins that either act as competitive binders of Wnts, notably the sFRP family of proteins, or act at the level of Lrp5; including the osteocyte specific protein, sclerostin (the Sost gene product) (73)(32), Wise (52) and the D”
Secreted and transmembrane wnt inhibitors and activators. (2013, background): “SOSTantagonizes Wnt signaling by binding to the first two YWTD–EGF repeat domains of LRP5 and LRP6 (Li et al. 2005b; Semenov et al. 2005).”
Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease (2008, background): “Sclerostin and Dickkopf proteins interfere with Wnt activity and antagonise canonical signalling by binding to LRP5 or LRP6, whereas WIF1, Cerberus and SFRPs can interact directly with Wnt proteins (Kawano and Kypta, 2003; Li et al., 2005).”
Sclerostin Mediates Bone Response to Mechanical Unloading Through Antagonizing Wnt/β‐Catenin Signaling (2009, background): “gether with previous data that sclerostin bound to Lrp5/Lrp6 and inhibited Wnt/b-catenin signaling in vitro,((19,20)) strongly implied sclerostin was an antagonist of Wnt/b-catenin sig-”
Inflammatory bone loss: pathogenesis and therapeutic intervention (2012, background): “Sclerostin represents another inhibitor of osteoblast activation by interfering with the WNT signalling pathway but also by binding to and antagonizing BMP”