Structural insight into regulation of the Wnt/b-catenin signalling pathway by sclerostin: implications for osteoporosis treatment


Vaclav Veverka1, Alistair J. Henry2, Patrick M. Slocombe2, Andrew Ventom2, Barbara Mulloy3, Frederick W. Muskett1, Mariusz Muzylak2, Kevin Greenslade2, Adrian Moore2, Li Zhang4, Jianhua Gong4, Xueming Qian4, Chris Paszty4, Richard J. Taylor2, Martyn K. Robinson2 and Mark D. Carr1


1University of Leicester,UK; 2UCB-Celltech, UK; 3NIBSC, UK, and 4Amgen Inc, USA;


The secreted glycoprotein sclerostin has recently emerged as a key negative regulator of Wnt signalling in bone and has stimulated considerable interest as a potential target for therapeutics designed to treat conditions associated with low bone mass, such as osteoporosis. The structure determination of sclerostin resulted in the identification of a previously unknown binding site for heparin, which is suggestive of a functional role in localising sclerostin to the surface of target cells. The conserved N and C-terminal arms of sclerostin were found to be unstructured, highly flexible and unaffected by heparin binding, which suggests a role in stabilising interactions with target proteins. The ability of sclerostin to specifically bind heparin was confirmed by NMR titration experiments. Similarly, mapping of the binding site for an antibody that antagonises the effects of sclerostin on Wnt signalling in vitro, and stimulates bone formation in vivo, has identified a functionally important region of sclerostin, which is clearly involved in the modulation of Wnt signalling (1).


1.  V. Veverka et al., J. Biol. Chem., 284, (2009), 10890.