Sclerostin

Sclerostin

Sclerostin, the product of the SOST gene, was originally believed to be a non-classical Bone morphogenetic protein (BMP) antagonist. More recently Sclerostin has been identified as binding to LRP5/6 receptors and activating the Wnt signalling pathway More recently, it has been revealed that the antagonism of BMP-induced bone formation by sclerostin is mediated by Wnt signalling, but not BMP signalling pathways.

Mutations of Sclerostin is associated with the syndrome Sclerosteosis in which there is an abnormal increase in the growth of bones due to lack of normal Sclerostin expression by osteocytes. This acts upon osteoblasts in the bone in paracrine manner of unknown mechanism.

Currently an anti-Sclerostin antibody is under development for the treatment of osteoporosis by Amgen.

OsteoGeneX Inc is developing and commercializing first in class sclerostin small molecule inhibitors (www.osteogenex.com).

References

1- Discovery of Sclerostin interaction with LRP5 and LRP6 and modulation of Wnt pathway (March 2001) - Krumlauf and Ellies US 60/388,970, filed 04.06.2002
2- Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005 May 20;280(20):19883-7
3- Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, Krumlauf R., Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. J Bone Miner Res. 2006 Nov;21(11):1738-49.;
4-Rutger L van Bezooijen, J Peter Svensson, Daniël Eefting, Annemieke Visser, Geertje van der Horst, Marcel Karperien, Paul HA Quax, Harry Vrieling, Socrates E Papapoulos, Peter ten Dijke, Clemens WGM Löwik. Wnt but Not BMP Signaling Is Involved in the Inhibitory Action of Sclerostin on BMP-Stimulated Bone Formation. J Bone Miner Res, 2007; 22(1):19-28
4- Proceedings of the 36th International Sun Valley Workshop On Skeletal Tissue Biology July 30 - August 2, 2006 Sun Valley, Idaho, USA

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