Sclerostin is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''SOST''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. It is a secreted

glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...

with a

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

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 An osteocyte, an oblate-shaped type of bone cell with dendritic processes, is the most commonly found cell in mature bone. It can live as long as the organism itself. The adult human body has about 42 billion of them. Osteocytes do not divide an ...

but is also expressed in other tissues, and has anti-anabolic effects on bone formation.

Structure

The sclerostin protein, with a length of 213 residues, has a

secondary structure Protein secondary structure is the local spatial conformation of the polypeptide backbone excluding the side chains. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...

that has been determined by

protein NMR Nuclear magnetic resonance spectroscopy of proteins (usually abbreviated protein NMR) is a field of structural biology in which NMR spectroscopy is used to obtain information about the structure and dynamics of proteins, and also nucleic acids, and ...

to be 28%

beta sheet The beta sheet (β-sheet, also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gene ...

(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 Bone morphogenetic proteins (BMPs) are a group of growth factors also known as cytokines and as metabologens. Professor Marshall Urist and Professor Hari Reddi discovered their ability to induce the formation of bone and cartilage, BMPs are now ...

(BMP) antagonist. More recently, sclerostin has been identified as binding to LRP5/ 6 receptors and inhibiting the

Wnt signaling pathway In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the ...

. 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

s and some

chondrocyte Chondrocytes (, ) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word '' chondroblast'' is commonly used to describe an immatu ...

s and it inhibits bone formation by

osteoblast Osteoblasts (from the Greek combining forms for " bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts fu ...

s. Sclerostin production by osteocytes is inhibited by parathyroid hormone, mechanical loading,

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

and cytokines including prostaglandin E₂,

oncostatin M Oncostatin M, also known as OSM, is a protein that in humans is encoded by the ''OSM'' gene. OSM is a pleiotropic cytokine that belongs to the interleukin 6 group of cytokines. Of these cytokines it most closely resembles leukemia inhibitory f ...

cardiotrophin-1 Cardiotrophin-1 (CT-1) is a cytokine. It is a cardiac hypertrophic factor of 21.5 kDa and a protein member of the IL-6 cytokine family. Pathology CT-1 is associated with the pathophysiology of heart diseases, including hypertension, myocardia ...

and

leukemia inhibitory factor Leukemia inhibitory factor, or LIF, is an interleukin 6 class cytokine that affects cell growth by inhibiting differentiation. When LIF levels drop, the cells differentiate. Function LIF derives its name from its ability to induce the termina ...

. Sclerostin production is increased by

calcitonin Calcitonin is a 32 amino acid peptide hormone secreted by parafollicular cells (also known as C cells) of the thyroid (or endostyle) in humans and other chordates in the ultimopharyngeal body. It acts to reduce blood calcium (Ca2+), opposing the ...

. Thus, osteoblast activity is self regulated by a negative feedback system.

Clinical significance

Mutations in the gene that encodes the sclerostin protein are associated with disorders associated with high bone mass,

sclerosteosis 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 ...

and van Buchem disease. van Buchem disease is 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. In the late 1990s, scientists at the company Chiroscience and the

University of Cape Town The University of Cape Town (UCT) (, ) is a public university, public research university in Cape Town, South Africa. Established in 1829 as the South African College, it was granted full university status in 1918, making it the oldest univer ...

determined that a "single mutation" in the gene was responsible for the disorder.

Sclerostin antibody

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 An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...

from

Amgen Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical Corporation, company headquartered in Thousand Oaks, California. As one of the world's largest independent biotechnology companies, Amgen has a ...

( 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 Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed to treat osteoporosis. Evidence shows that they reduce the risk of fracture in ...

and teriparatide treatment; it had mild injection side effects. A Phase II trial of a monoclonal human antibody to sclerostin from

Eli Lilly Eli Lilly (July 8, 1838 – June 6, 1898) was a Union Army officer, pharmacist, chemist, and businessman who founded Eli Lilly and Company. Lilly enlisted in the Union Army during the American Civil War and recruited a company of men to ...

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. 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. Sclerostin has significance within the field of dentistry and regenerative strategies which target sclerostin are in development. In April 2019, the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

approved Romosozumab for use in women with a very high risk of osteoporotic fracture. It was also approved for use in Japan and the European Union in 2019.

References

External links