Disease relevance of SOST

• Here we link these two pathways by demonstrating, via gel shift and transient transfection analyses, that Cbfa1 binding to the proximal SOST promoter contributes to differential SOST expression in two osteosarcoma cell lines [1].
• A generalized skeletal hyperostosis in two siblings caused by a novel mutation in the SOST gene [2].
• Reduced bone resorption occurs due to faulty activity of the sclerostin molecule, a product of the recently discovered SOST gene in chromosome 17 [3].
• Sclerosteosis is an autosomal recessive sclerosing bone dysplasia characterized by progressive skeletal overgrowth [4].
• Sclerosteosis is a unique autosomal recessive condition in which skeletal overgrowth is associated with syndactyly and digital malformation [5].

High impact information on SOST

• SOST expression was detected in cultured osteoblasts and in mineralizing areas of the skeleton, but not in osteoclasts [6].
• The clinical and radiographic stigmata of sclerosteosis permit differentiation from the other disorders of the "osteopetrosis" or "Albers-Schönberg disease" group, in which bony thickening and cranial nerve palsy occur [5].
• We studied whether the sclerosteosis/van Buchem disease gene (SOST) is an osteoporosis-risk gene by examining its association with bone-mineral density (BMD) [7].
• We used a set of eight polymorphisms from the SOST gene region to genotype 1,939 elderly men and women from a large population-based prospective-cohort study of Dutch whites [7].
• Mutations in SOST result in sclerosteosis, and alterations in the SOST gene expression may be causal in the closely related van Buchem disease [7].

Chemical compound and disease context of SOST

• Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein [4].

Biological context of SOST

• In Xenopus and mammalian cell culture assays, we showed that SOST is able to attenuate Wnt signaling and that this attenuation can be rescued by the addition of alpha-Sost antibodies or by the introduction of single amino acid substitution that alter its binding to LRP6 [8].
• SOST, a novel bone morphogenetic protein (BMP) antagonist and negative regulator of bone formation, is expressed in osteogenic cells [9].
• We did not find association between any of several frequent haplotypes across the SOST gene region and BMD [7].
• A 3-bp insertion (f=0.38) in the presumed SOST promoter region (SRP3) was associated with decreased BMD in women at the femoral neck (FN) (P=.05) and lumbar spine (LS) (P=.01), with evidence of an allele-dose effect in the oldest age group (P=.006) [7].
• A null mutation in the SOST gene is associated with sclerosteosis, an inherited disorder characterized by a high bone mass phenotype [10].

Anatomical context of SOST

• These findings show that the levels of SOST are modulated by BMPs and the interactions of the BMPs with steroid hormones in human osteoblasts [9].
• Sclerosteosis is an autosomal recessive disease that is characterized by overgrowth of bone tissue and is linked to mutations in the gene encoding the secreted protein SOST [11].
• In the present study, we show that SOST, a Dan family member reported to antagonize BMP and Wnt activity, is expressed within the medial vessel wall of the great arteries containing smooth muscle cells [12].
• The ascending aorta, aortic arch, brachiocephalic artery, common carotids, and pulmonary trunk were all associated with SOST expressing smooth muscle cells, while the heart itself, including the valves, and more distal arteries, that is, pulmonary arteries, subclavian arteries, and descending aorta, were negative [12].
• New evidence indicating that downregulation of an osteocyte signal (sclerostin, the SOST gene product) occurs in response to intermittent PTH has rekindled interest in the key role played by osteocytes and bone-lining cells in co-ordinating surface anabolic activity [13].

Associations of SOST with chemical compounds

• BMP's stimulatory effects on SOST were further enhanced by retinoic acid or 1,25-dihydroxyvitamin D3 [9].
• In contrast, dexamethasone (DEX) blocked the effects of the BMPs on SOST and gremlin, but not on noggin [9].
• We compared and contrasted the mechanism of action for the cysteine knot protein subfamily, Wise and Sost (Sclerostin) [8].
• 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 stabilizing interactions with target proteins [14].

Physical interactions of SOST

• LRP5 Mutations Linked to High Bone Mass Diseases Cause Reduced LRP5 Binding and Inhibition by SOST [15].

Other interactions of SOST

• A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population [16].
• Downregulation of SOST/Sclerostin by PTH: A novel mechanism of hormonal control of bone formation mediated by osteocytes [17].
• Sclerosteosis shares remarkable similarities with "high bone mass" diseases caused by "gain-of-function" mutations in the LRP5 gene, which encodes a coreceptor for Wnt signaling proteins [11].

Analytical, diagnostic and therapeutic context of SOST

• Epitope tagged cell supernatants containing either Sost or soluble mutant or wildtype LRP5/LRP6 were used for immunoprecipitation [8].
• We identified 26 different polymorphisms in the SOST gene and selected 5 of these for association analysis in a case-control study of 619 women with either high or low BMD, drawn from a random population-based survey of 5119 perimenopausal white women [18].
• The radiological picture of van Buchem disease closely resembles sclerosteosis, although in the latter patients, syndactyly, tall stature, and raised intracranial pressure are frequently observed, allowing a differential diagnosis with van Buchem disease [2].
• Sclerosteosis is a rare autosomal recessive condition which is characterized by excessive skeletal overgrowth, distortion of the facies, cranial nerve abnormalities and raised intracranial pressure [19].

References