Sclerostin

For other uses, see SOST (disambiguation).

Sclerostin
250px NMR structure of mouse sclerostin.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2K8P, 3SOV
Identifiers
Symbols	SOST ; CDD; SOST1; VBCH
External IDs	OMIM: 605740 MGI: 1921749 HomoloGene: 11542 GeneCards: SOST Gene
Gene ontology Molecular function • protein binding • transcription factor binding • heparin binding Cellular component • extracellular region • proteinaceous extracellular matrix • extracellular space • Golgi apparatus • extracellular matrix Biological process • ossification • response to mechanical stimulus • Wnt signaling pathway • negative regulation of ossification • negative regulation of BMP signaling pathway • negative regulation of protein complex assembly • positive regulation of transcription, DNA-templated • cellular response to parathyroid hormone stimulus • negative regulation of canonical Wnt signaling pathway • negative regulation of Wnt signaling pathway involved in dorsal/ventral axis specification Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	50964	74499
Ensembl	ENSG00000167941	ENSMUSG00000001494
UniProt	Q9BQB4	Q99P68
RefSeq (mRNA)	NM_025237	NM_024449
RefSeq (protein)	NP_079513	NP_077769
Location (UCSC)	Chr 17: 43.75 – 43.76 Mb	Chr 11: 101.96 – 101.97 Mb
PubMed search	[1]	[2]

Sclerostin
Identifiers
Symbol	Sclerostin
Pfam	PF05463
InterPro	IPR008835
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

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

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 by the 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% 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 bone morphogenetic protein (BMP) antagonist. More recently sclerostin has been identified as binding to LRP5/6 receptors and inhibiting the 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 osteocytes and some chondrocytes and it inhibits bone formation by osteoblasts.

Sclerostin production by osteocytes is inhibited by parathyroid hormone, mechanical loading and cytokines including prostaglandin E2, oncostatin M, cardiotrophin-1 and leukemia inhibitory factor. Sclerostin production is increased by 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 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 skull, mandible and tubular bones. It can cause facial distortion and syndactyly. Increased intracranial pressure can cause sudden death in patients. It is a rare disorder that is most prominent in the Afrikaner population in 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 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 antibody from Amgen (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 bisphosphonate and 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.

External links

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

• PDB: 2KD3​;
• http://users.telenet.be/zeldzame.ziekten/List.o/Pmenoposteo.htm