Sclerostin

Sclerostin is a protein that in humans is encoded by the SOST gene.^[1][2]

Sclerostin is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN (differential screening-selected gene aberrative in neuroblastoma) family of bone morphogenetic protein (BMP) antagonists. Sclerostin is produced primarily by the osteocyte but is also expressed in other tissues,^[3] and has anti-anabolic effects on bone formation.^[4]

Structure[edit | edit source]

The sclerostin protein, with a length of 213 residues, has a secondary structure that has been determined by protein NMR to be 28% beta sheet (6 strands; 32 residues).^[5]

Function[edit | edit source]

Sclerostin, the product of the SOST gene, located on chromosome 17q12–q21 in humans,^[6] was originally believed to be a non-classical bone morphogenetic protein (BMP) antagonist.^[7] More recently, sclerostin has been identified as binding to LRP5/6 receptors and inhibiting the Wnt signaling pathway.^[8][9] The inhibition of the Wnt pathway leads to decreased bone formation.^[8] Although the underlying mechanisms are unclear, it is believed that the antagonism of BMP-induced bone formation by sclerostin is mediated by Wnt signaling, but not BMP signaling pathways.^[10][11] Sclerostin is expressed in osteocytes and some chondrocytes and it inhibits bone formation by osteoblasts.^[12][13][14]

Sclerostin production by osteocytes is inhibited by parathyroid hormone,^[14][15] mechanical loading^[16] and cytokines including prostaglandin E2,^[17] oncostatin M, cardiotrophin-1 and leukemia inhibitory factor.^[18] Sclerostin production is increased by calcitonin.^[19] Thus, osteoblast activity is self regulated by a negative feedback system.^[20]

Clinical significance[edit | edit source]

Mutations in the gene that encodes the sclerostin protein are associated with disorders associated with high bone mass, sclerosteosis and van Buchem disease.^[6]

van Buchem disease is also an autosomal recessive skeletal disease characterized by bone overgrowth.^[21] It was first described in 1955 as "hyperostosis corticalis generalisata familiaris", but was given the current name in 1968.^[21][22] Excessive bone formation is most prominent in the skull, mandible, clavicle, ribs and diaphyses of long bones and bone formation occurs throughout life.^[21] It is a very rare condition with about 30 known cases in 2002.^[21] In 1967 van Buchem characterized the disease in 15 patients of Dutch origin.^[21] Patients with sclerosteosis are distinguished from those with van Buchem disease because they are often taller and have hand malformations.^[23] In the late 1990s, scientists at the company Chiroscience and the University of Cape Town determined that a "single mutation" in the gene was responsible for the disorder.^[24]

An antibody for sclerostin is being developed because of the protein’s specificity to bone.^[12] Its use has increased bone growth in preclinical trials in osteoporotic rats and monkeys.^[25][26] In a Phase I study, a single dose of anti-sclerostin antibody from Amgen (Romosozumab) increased bone density in the hip and spine in healthy men and postmenopausal women and the drug was well tolerated.^[27] In a Phase II trial, one year of the antibody treatment in osteoporotic women increased bone density more than bisphosphonate and teriparatide treatment; it had mild injection side effects.^[13][28] A Phase II trial of a monoclonal human antibody to sclerostin from Eli Lilly had positive effects on post-menopausal women. Monthly treatments of the antibody for one year increased the bone mineral density of the spine and hip by 18 percent and 6 percent, respectively, compared to the placebo group.^[29] In a Phase III trial, one year of Romosozumab treatment in post-menopausal women reduced the risk of vertebral fractures compared to the placebo group. It also increased the bone mineral density in the lumbar spine (13.3% versus 0.0%), femoral neck (5.2% versus -0.7%) and total hip (6.8% versus 0.0%) compared to the placebo group. Adverse events were balanced between the groups.^[30]

References[edit | edit source]

Further reading[edit | edit source]

External links[edit | edit source]

• GeneReview/NCBI/NIH/UW entry on SOST-Related Sclerosing Bone Dysplasias