Sclerostin

Sclerostin is a is_associated_with::protein that in humans is encoded by the SOST is_associated_with::gene.

Sclerostin is a secreted is_associated_with::glycoprotein with a C-terminal is_associated_with::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 by the is_associated_with::osteocyte and has anti-anabolic effects on bone formation.

Structure
The sclerostin protein, with a length of 213 residues, has a dssp secondary structure that is 28% is_associated_with::beta sheet (6 strands; 32 residues).

Function
Sclerostin, the product of the SOST gene, located on chromosome 17q12–q21 in humans, was originally believed to be a non-classical is_associated_with::bone morphogenetic protein (BMP) antagonist. More recently sclerostin has been identified as binding to is_associated_with::LRP5/6 receptors and inhibiting the is_associated_with::Wnt signaling pathway. The inhibition of the Wnt pathway leads to decreased bone formation. 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. Sclerostin is expressed in is_associated_with::osteocytes and some is_associated_with::chondrocytes and it inhibits bone formation by is_associated_with::osteoblasts.

Sclerostin production by osteocytes is inhibited by is_associated_with::parathyroid hormone, mechanical loading and cytokines including prostaglandin E2, is_associated_with::oncostatin M, is_associated_with::cardiotrophin-1 and is_associated_with::leukemia inhibitory factor. Sclerostin production is increased by is_associated_with::calcitonin. Thus, osteoblast activity is self regulated by a negative feedback system.

Clinical significance
Mutations in the gene sclerostin are associated with disorders associated with high bone mass, sclerosteosis and van Buchem disease. Sclerosteosis is an is_associated_with::autosomal recessive disorder characterized by bone overgrowth. It was first described in 1958 but given the current name in 1967. Excessive bone formation is most prominent in the is_associated_with::skull, is_associated_with::mandible and tubular bones. It can cause facial distortion and is_associated_with::syndactyly. Increased intracranial pressure can cause sudden death in patients. It is a rare disorder that is most prominent in the is_associated_with::Afrikaner population in is_associated_with::South Africa (40 patients), but there have also been cases of American and Brazilian families.

van Buchem disease is also an autosomal recessive skeletal disease characterized by bone overgrowth. It was first described in 1955 as "hyperostosis corticalis generalisata familiaris", but was given the current name in 1968. Excessive bone formation is most prominent in the skull, mandible, clavicle, ribs and is_associated_with::diaphyses of long bones and bone formation occurs throughout life. It is a very rare condition with about 30 known cases in 2002. In 1967 van Buchem characterized the disease in 15 patients of Dutch origin. Patients with sclerosteosis are distinguished from those with van Buchem disease because they are often taller and have hand malformations.

An antibody for sclerostin is being developed because of the protein’s specificity to bone. Its use has increased bone growth in preclinical trials in osteoporotic rats and monkeys. In a Phase I study, a single dose of anti-sclerostin is_associated_with::antibody from is_associated_with::Amgen (is_associated_with::Romosozumab) increased bone density in the hip and spine in healthy men and postmenopausal women and the drug was well tolerated. In a Phase II trial, one year of the antibody treatment in osteoporotic women increased bone density more than is_associated_with::bisphosphonate and is_associated_with::teriparatide treatment; it had mild injection side effects. 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.

The Amgen drug is expected to be on the market in 2017 and is predicted to be the gold standard in osteoporosis treatment by 2021. In addition, OsteoGeneX is developing small molecule inhibitors of sclerostin.