Osteoprotegerin also known as osteoclastogenesis inhibitory factor (OCIF), or tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), is a protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 that in humans is encoded by the TNFRSF11B gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

. Osteoprotegerin is a cytokine receptor
Cytokine receptor
Cytokine receptors are receptors that bind cytokines.In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly because a deficiency of cytokine receptors has now been...

, and a member of the tumor necrosis factor
Tumor necrosis factors
Tumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...

 (TNF) receptor superfamily.


Osteoprotegerin is a basic glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...

 comprising 401 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 residues arranged into 7 structural domains. It is found as either a 60-kDa monomer or 120-kDa dimer linked by disulfide bonds.


Osteoprotegerin is a decoy receptor for the receptor activator of nuclear factor kappa B ligand (RANKL
Receptor activator of nuclear factor kappa-B ligand , also known as tumor necrosis factor ligand superfamily member 11 , TNF-related activation-induced cytokine , osteoprotegerin ligand , and osteoclast differentiation factor , is a protein that in humans is encoded by the TNFSF11 gene.RANKL is...

). By binding RANKL, OPG inhibits nuclear kappa B (NF-κB) which is a central and rapid acting transcription factor for immune-related genes, and a key regulator of inflammation, innate immunity, and cell survival and differentiation.
Osteoprotegerin levels are influenced by voltage-dependent calcium channels Cav1.2.
OPG can reduce the production of osteoclasts, by inhibiting the differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...

 of osteoclast precursors (osteoclasts are related to monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...

Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...

s and are derived from granulocyte/macrophage-forming colony units (CFU-GM)) into osteoclasts and also regulates the resorption of osteoclasts in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...

and in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

. OPG binding to RANKL on osteoblast
Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen...

/stromal cells, blocks the RANKL-RANK
Receptor Activator of Nuclear Factor κ B , also known as TRANCE Receptor, is a type I membrane protein that is expressed on the surface of osteoclasts and is involved in their activation upon ligand binding...

In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...

 interaction between osteoblast/stromal cells and osteoclast precursors. This has the effect of inhibiting the differentiation of the osteoclast precursor into a mature osteoclast.

Regulation and therapeutic applications

Osteoprotegerin production is stimulated in vivo by the female sex hormone estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...

, as well as the osteoporosis drug, strontium ranelate
Ranelic acid
Ranelic acid is an organic acid capable of chelating metal cations.It forms the ranelate ion, C12H6N2O8S4-. Strontium ranelate, made by combining strontium with ranelic acid, is a drug used to treat osteoporosis and increase bone mineral density ....

. Denosumab
Denosumab is a fully human monoclonal antibody for the treatment of osteoporosis, treatment induced bone loss, bone metastases, rheumatoid arthritis, multiple myeloma and giant cell tumor of bone. It was developed by the company Amgen....

 is a pharmacologic agent that in essence acts like osteoprotegerin as both act as decoy receptors for osteoblastic RANKL.

Recombinant human osteoprotegerin specifically acts on bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...

, increasing bone mineral density and bone volume. Space shuttle flight STS-108 in 2001 tested the effects of osteoprotegerin on mice in microgravity, finding that it did prevent increase in resorption and maintained mineralization. Osteoprotegerin has been used experimentally to decrease bone resorption in women with postmenopausal osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...

 and in patients with lytic bone metastases
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...


Clinical significance

Elevated OPG levels has been reported in heart diseases and in severe mental disorders.

Further reading

  • Blázquez-Medela AM, López-Novoa JM, Martínez-Salgado C.Osteoprotegerin and diabetes-associated pathologies.Curr Mol Med. 2011 Jul 1;11(5):401-16. Review.PMID: 21568931
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