The Journal of Bone and Joint Surgery (American). 2008;90:31-35.
doi:10.2106/JBJS.G.01183
© 2008 The Journal of Bone and Joint Surgery, Inc.
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Osteocyte-Derived Sclerostin Inhibits Bone Formation: Its Role in Bone Morphogenetic Protein and Wnt Signaling

Peter ten Dijke, PhD, Carola Krause, MS, David J. J. de Gorter, MS, Clemens W.G.M. Löwik, PhD and Rutger L. van Bezooijen, PhD

Corresponding author:
Peter ten Dijke, PhD
Department of Molecular Cell Biology, Building 2, Room R-02-022, Leiden University Medical Center, Postzone S-1-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
E-mail address: p.ten_dijke{at}lumc.nl

Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from the Dutch Organization for Scientific Research (NWO 918.66.606) and the European Commission (LSHM-CT-2003-503020). Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

Sclerosteosis and Van Buchem disease are rare, high-bone-mass disorders that have been linked to deficiency in the SOST gene, encoding sclerostin. Sclerostin belongs to the DAN family of glycoproteins, of which multiple family members have been shown to antagonize bone morphogenetic protein (BMP) and/or Wnt activity. Sclerostin is specifically expressed by osteocytes and inhibits BMP-induced osteoblast differentiation and ectopic bone formation. Sclerostin binds only weakly to BMPs and does not inhibit direct BMP-induced responses. Instead, sclerostin antagonizes canonical Wnt signaling by binding to Wnt coreceptors, low-density lipoprotein receptor-related protein 5 and 6. Several lipoprotein receptor-related protein-5 mutants that cause the high-bone-mass trait are defective in sclerostin binding. Thus, high bone mass in sclerosteosis and Van Buchem disease may result from increased Wnt signaling due to the absence of or insensitivity to sclerostin.


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Sclerostin Inhibitors Have Potential to Enhance Fixation of Implants
Adam M Hill, et al.
JBJS Online, 10 Apr 2008 [Full text]