Sclerostin (SOST), a glycoprotein predominantly secreted by bone tissue osteocytes, is an important regulator of bone formation, and loss of <i>SOST</i> results in Van Buchem disease.
Finally, high BMD is a feature of many genetic diseases, most notably osteopetrosis and the disorders caused by mutations in the sclerostin gene SOST (sclerosing bone dysplasia and van Buchem disease) or in the LRP5 gene encoding the low-density lipoprotein receptor-related protein 5 (which is the Wnt co-receptor).
Here we describe how human genetics studies in sclerosteosis and VBD patients, in combination with the generation of transgenic and knockout mice, has led to a better understanding of the role of sclerostin in bone metabolism.
High-bone-mass phenotypes in patients with loss-of-function mutations in the LRP5/6 inhibitor Sost (sclerosteosis), or in its downstream enhancer region (van Buchem disease), highlight the utility of targeting Sost/sclerostin to improve bone properties.
The BMD GWAS lead SNPs rs7220711 and rs1107748 both reside in the 52-kb regulatory element deletion 35-kb downstream of the SOST gene which leads to Van Buchem disease.
In this article we review the demographic, clinical, biochemical, radiological, and histological characteristics of patients with sclerosteosis and van Buchem disease that led to a better understanding of the role of sclerostin in bone metabolism in humans and we discuss the relevance of these findings for the development of new therapeutics for the treatment of patients with osteoporosis.
Loss of sclerostin gene function is related to 3 different craniotubular hyperostosis processes: sclerosteosis, craniodiaphyseal dysplasia, and van Buchem disease.
After discovering that lack of Sost/sclerostin expression is the cause of the high bone mass human syndromes Van Buchem disease and sclerosteosis, extensive animal experimentation and clinical studies demonstrated that sclerostin plays a critical role in bone homeostasis and that its deficiency or pharmacological neutralization increases bone formation.
Sclerosteosis and Van Buchem disease are two rare bone sclerosing disorders characterized by increased bone mineral density, tall stature and entrapment of cranial nerves due to overgrowth of a highly dense bone.
Furthermore, we discuss provocative reports suggesting novel approaches through inhibitors of this pathway to treat rarer diseases such as Osteoporosis-Pseudoglioma Syndrome (OPPG), Osteogenesis Imperfecta (OI), and Sclerosteosis/Van Buchem disease.
Sclerostin was first identified in the study of two rare autosomal recessive disorders, sclerosteosis and van Buchem disease, which are associated with absent or reduced levels of sclerostin.
Unlike the other SOST-related conditions, sclerosteosis and Van Buchem disease that are inherited as recessive traits seem to be caused by a dominant negative mechanism.
The restricted expression pattern of sclerostin in the skeleton and the exclusive bone phenotype of good quality of patients with sclerosteosis and van Buchem disease provide the basis for the design of therapeutics that stimulate bone formation.
Mutation analysis of the complete coding region and flanking highly conserved sequences of SOST, evaluation of the presence of the 52-kb deletion associated with Van Buchem disease in Dutch patients and mutation analysis of exons 2-4 of LRP5, and the coding regions of DKK1 and KRM1 did not reveal any disease-causing mutations.
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.
We have previously identified a distant enhancer within the 52-kb Van Buchem disease deletion downstream of the SOST gene that is essential for its expression in adult bone.
The exclusive bone phenotype of good quality of patients with sclerosteosis and Van Buchem disease and the specific localization of sclerostin make it an attractive target for the development of bone forming therapeutics.
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.
MEOX1 is known to be important for the development of the axial skeleton, whereas the SOST gene is the determinant of sclerosteosis, a disorder that shares many features with van Buchem disease, thus raising the possibility that van Buchem disease results from dysregulation of the expression of one or both of these genes.
Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients.