title: Identification of the disease-causing gene in sclerosteosis--discovery of a novel bone anabolic target?
abstract: Genetic studies recently unraveled the genetic cause of sclerosteosis, a rare skeletal dysplasia characterized by a generalized increase in bone mass. Different loss-of-function mutations were identified in SOST, a gene with no homology to any known gene. This SOST gene is also involved in the pathogenesis of van Buchem disease, a disorder closely resembling sclerosteosis, since a 52-kb deletion located downstream of SOST is found in patients diagnosed with this condition. Molecular studies showed a very restricted expression pattern of SOST and its gene product, sclerostin, with areas in the bone tissue, more precisely in cells of the osteoblast lineage, being the major sites of expression. Sclerostin is a secreted protein with a cysteine knot motif. In vitro studies demonstrated that sclerostin acts as a modulator of BMP signaling by binding to different members of the BMP growth factor family and acting on downstream BMP signal transduction events. The important function of sclerostin in bone metabolism has also been proven in vivo by the osteopenic phenotype of transgenic mice overexpressing SOST in bone. The identification of sclerostin as an important protein in bone metabolism opens new perspectives for the development of anabolic therapeutics to prevent and treat osteoporosis.
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: W
authors.initials: W
authors.lastname: Balemans
authors.forename: W
authors.initials: W
authors.lastname: Van Hul
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000378:metabolism*; D001842:Bone and Bones / Q000378:metabolism / Q000503:physiopathology; D005819:Genetic Markers / Q000235:genetics*; D006801:Humans; D010026:Osteosclerosis / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C422903:SOST protein, human