Top Qs
Timeline
Chat
Perspective
Sclerostin
Protein-coding gene in the species Homo sapiens From Wikipedia, the free encyclopedia
Remove ads
Sclerostin is a protein that in humans is encoded by the SOST gene.[5] It 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,[6] and has anti-anabolic effects on bone formation.[7]
Remove ads
Structure
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).[8]
Function
Sclerostin, the product of the SOST gene, located on chromosome 17q12–q21 in humans,[9] was originally believed to be a non-classical bone morphogenetic protein (BMP) antagonist.[10] More recently, sclerostin has been identified as binding to LRP5/6 receptors and inhibiting the Wnt signaling pathway.[11][12] The inhibition of the Wnt pathway leads to decreased bone formation.[11] 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.[13][14] Sclerostin is expressed in osteocytes and some chondrocytes and it inhibits bone formation by osteoblasts.[15][16][17]
Sclerostin production by osteocytes is inhibited by parathyroid hormone,[17][18] mechanical loading,[19] estrogen[20] and cytokines including prostaglandin E2,[21] oncostatin M, cardiotrophin-1 and leukemia inhibitory factor.[22] Sclerostin production is increased by calcitonin.[23] Thus, osteoblast activity is self regulated by a negative feedback system.[24]
Remove ads
Clinical significance
Summarize
Perspective
Mutations in the gene that encodes the sclerostin protein are associated with disorders associated with high bone mass, sclerosteosis and van Buchem disease.[9]
van Buchem disease is an autosomal recessive skeletal disease characterized by bone overgrowth.[25] It was first described in 1955 as "hyperostosis corticalis generalisata familiaris", but was given the current name in 1968.[25][26] Excessive bone formation is most prominent in the skull, mandible, clavicle, ribs and diaphyses of long bones and bone formation occurs throughout life.[25] It is a very rare condition with about 30 known cases in 2002.[25] In 1967 van Buchem characterized the disease in 15 patients of Dutch origin.[25] Patients with sclerosteosis are distinguished from those with van Buchem disease because they are often taller and have hand malformations.[27] 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.[28]
Sclerostin antibody
An antibody for sclerostin is being developed because of the protein's specificity to bone.[15] Its use has increased bone growth in preclinical trials in osteoporotic rats and monkeys.[29][30] 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.[31] 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.[16][32] 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.[33] 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.[34] Sclerostin has significance within the field of dentistry[35] and regenerative strategies which target sclerostin are in development.[36] In April 2019, the Food and Drug Administration approved Romosozumab for use in women with a very high risk of osteoporotic fracture.[37] It was also approved for use in Japan[38] and the European Union in 2019.[39]
Remove ads
References
Further reading
External links
Wikiwand - on
Seamless Wikipedia browsing. On steroids.
Remove ads