Osteocyte-derived sclerostin inhibits bone formation: its role in bone morphogenetic protein and Wnt signaling.
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.
ten Dijke
Peter
P
Department of Molecular Cell Biology, Building 2, Room R-02-022, Leiden University Medical Center, Postzone S-1-P, PO Box 9600, 2300 RC Leiden, The Netherlands. p.ten_dijke@lumc.nl
Krause
Carola
C
de Gorter
David J J
DJ
Löwik
Clemens W G M
CW
van Bezooijen
Rutger L
RL
D048868:Adaptor Proteins, Signal Transducing; D015519:Bone Density; D001848:Bone Diseases, Developmental / Q000235:genetics*; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000502:physiology*; D005819:Genetic Markers / Q000235:genetics* / Q000502:physiology; D006801:Humans; D010011:Osteocytes / Q000502:physiology*; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C422903:SOST protein, human; D051153:Wnt Proteins