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Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF) or tumour necrosis factor receptor superfamily member 11B (TNFRSF11B), is a
cytokine receptor Cytokine receptors are receptors that bind to 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 be ...
of the tumour necrosis factor (TNF) receptor superfamily encoded by the ''TNFRSF11B'' gene. OPG was first discovered as a novel secreted TNFR related protein that played a role in the regulation of bone density and later for its role as a decoy receptor for receptor activator of nuclear factor kappa-B ligand (
RANKL Receptor activator of nuclear factor kappa- ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiati ...
). OPG also binds to TNF-related apoptosis-inducing ligand (
TRAIL A trail, also known as a path or track, is an unpaved lane or small road usually passing through a natural area. In the United Kingdom and the Republic of Ireland, a path or footpath is the preferred term for a pedestrian or hiking trail. ...
) and inhibits TRAIL induced apoptosis of specific cells, including tumour cells. Other OPG ligands include
syndecan-1 Syndecan 1 is a protein which in humans is encoded by the ''SDC1'' gene. The protein is a transmembrane (type I) heparan sulfate proteoglycan and is a member of the syndecan proteoglycan family. The syndecan-1 protein functions as an integral ...
,
glycosaminoglycans Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case ...
,
von Willebrand factor Von Willebrand factor (VWF) () is a blood glycoprotein involved in hemostasis, specifically, platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases, including thrombotic thrombocytope ...
, and
factor VIII Factor VIII (FVIII) is an essential blood-clotting protein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the ''F8'' gene. Defects in this gene result in hemophilia A, a recessive X-linked coagulation disorder ...
-von Willebrand factor complex. OPG has been identified as having a role in tumour growth and metastasis, heart disease, immune system development and signalling, mental health, diabetes, and the prevention of
pre-eclampsia Pre-eclampsia is a disorder of pregnancy characterized by the onset of high blood pressure and often a significant amount of protein in the urine. When it arises, the condition begins after 20 weeks of pregnancy. In severe cases of the disease ...
and
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone a ...
during pregnancy.


Biochemistry

OPG is largely expressed by
osteoblast Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...
lineage cells of bone, epithelial cells of the gastrointestinal tract, lung, breast and skin, vascular endothelial cells, as well as
B-cells B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
and
dendritic cells Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...
in the immune system. OPG is a soluble glycoprotein which can be found as either a 60-kDa monomer or a 120-kDa dimer linked by disulfide bonds. The dimerisation of OPG is necessary for RANK-RANKL inhibition as dimerisation increases the affinity of OPG for RANKL (from a KD of 3µM as a monomer to 10nM as a dimer). As a monomer, OPG would have insufficient affinity for RANKL to compete with RANK and effectively suppress RANK-RANKL interactions. OPG proteins are made up of 380
amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
which form seven functional domains. Domains 1-4 are cysteine-rich N-terminal domains that interact with RANKL during binding. Domains 5-6 are death domains that contribute to the dimerisation of OPG. Domain 7 is a C-terminal heparin-binding domain ending with a cysteine (Cys-400) which also plays an important role in the dimerisation of OPG. OPG expression can be upregulated by IL-1β, 1α,25(OH)2D3, Wnt/β-catenin signalling through Wnt16, Wnt4 and Wnt3a TNFα and estrogen. OPG expression can also be upregulated transcriptionally through DNA binding sites for estrogen receptor α (ER-α) and TCF in the promoter region of the OPG gene. Downregulation of OPG can be effected by TGF-β1, PTH and DNA methylation of a CpG island in the OPG gene.


Estrogen and OPG regulation

OPG expression in osteoblast lineage cells is highly regulated by
estrogens Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
such as
estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...
(E2). E2 transcriptionally regulates OPG expression through binding
estrogen receptors Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors ( ERα and ERβ), which are members of the ...
(predominantly ER-α) on osteoblast lineage cell surfaces. The E2-ERα complex then translocates into the cell nucleus where it binds an estrogen response element in the promoter region of the OPG gene to upregulate OPG mRNA transcription. Estrogens can also post-transcriptionally regulate OPG protein expression through the suppression of the
microRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. mi ...
(miRNA) miR-145. miR-145 binds miRNA binding sites in the 3’UTR of OPG mRNA transcripts and suppresses the translation of OPG proteins. Estrogen binds its ER-β receptor on the cell surface to suppress many miRNAs, including miR-145, thus blocking inhibition of OPG mRNA translation. Estrogen suppresses osteoclastogenesis through the upregulation of OPG expression in osteoblast lineage cells. Androgens such as testosterone and DHT also inhibit osteoclastogenesis, however androgens act directly through androgen receptors on osteoclast precursor cells without affecting OPG expression in osteoblasts. Further, in the absence of
aromatase Aromatase (), also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily, which are monooxygenases that catalyze many ...
enzymes converting testosterone into estrogen, testosterone and DHT downregulate OPG mRNA expression.


Function

OPG plays an important role in bone metabolism as a decoy receptor for RANKL in the RANK/RANKL/OPG axis, inhibiting osteoclastogenesis and bone resorption. OPG has also been shown to bind and inhibit TNF-related apoptosis-inducing ligand (TRAIL) which is responsible for inducing apoptosis in tumour, infected and mutated cells.


Bone metabolism

The RANK/RANKL/OPG axis is a critical pathway in maintaining the symbiosis between bone resorption by osteoclasts and bone formation by osteoblasts. RANKL is released by osteoblast lineage cells and binds to receptor RANK on the surface of osteoclast progenitor cells RANK-RANKL binding activates the nuclear factor kappa B (NF-κB) pathway resulting in the upregulation of the transcription factor nuclear factor of activated T-cells cytoplasmic 1 ( NFATc1). NFATc1 is a master regulator for the expression of essential cytokines during the differentiation of osteoclast precursor cells into mature osteoclasts, known as osteoclastogenesis. Mature osteoclasts then bind to bone through tight junctions and release digestive enzymes to resorb the old bone. As bone is resorbed, collagen and minerals are released into the local microenvironment creating both the space and minerals needed for osteoblasts to lay down new bone. As a decoy receptor for RANKL, OPG inhibits RANK-RANKL interactions thus suppressing osteoclastogenesis and bone resorption. OPG is also a decoy receptor for TRAIL, another regulator of osteoclastogenesis in osteoclast precursor cells and an autocrine signal for mature osteoclast cell death. TRAIL induces osteoclastogenesis by binding to specific TRAIL receptors on osteoclast precursor cell surfaces, inducing
TRAF6 TRAF6 is a TRAF human protein. Function The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF recep ...
signalling, activating NF-κB signalling and upregulating NFATc1 expression. During osteoclastogenesis the different TRAIL receptors on the cell surface change resulting in an increase of apoptosis inducing TRAIL receptors expressed on mature osteoclasts. As a decoy receptor for both RANKL and TRAIL, OPG simultaneously suppresses osteoclastogenesis while also inhibiting TRAIL induced cell death of mature osteoclast cells. OPG has an equally high affinity for RANKL and TRAIL suggesting that it is equally effective at inducing osteoclastogenesis and inhibiting osteoclast apoptosis.


Disease


Atrophic nonunion shaft fractures

A normal steady state of bone metabolism seems to be present in patients with atrophic nonunion fractures, despite the high serum OPG. Only serum OPG was significantly higher in the patients compared to healed and healing controls. (49)


Osteoporosis

Osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone a ...
is a bone-related disease caused by increased rates of bone resorption compared to bone formation. A higher rate of resorption is often caused by increased osteoclastogenesis and results in symptoms of osteopenia such as excessive bone loss and low bone mineral density. Osteoporosis is often triggered in post-menopausal women due to reduced estrogen levels associated with the depletion of hormone-releasing ovarian follicles. Decreasing estrogen levels result in the downregulation of OPG expression and reduced inhibition of RANKL. Therefore RANKL can more readily bind to RANK and cause the increased osteoclastogenesis and bone resorption seen in osteoporosis. Decreased estrogen is a common cause of osteoporosis that can be seen in other conditions such as ovariectomy, ovarian failure, anorexia, and hyperprolactinaemia. Osteoblastic synthesis of bone does not increase to compensate for the accelerated bone resorption as the lower estrogen levels result in increased rates of osteoblast
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
. The higher rate of bone resorption compared to bone formation leads to the increased porosity and low bone mineral density of individuals with osteoporosis.


Cancer

Tumour endothelial cells have been found to express higher levels of OPG when compared to normal endothelial cells. When in contact with tumour cells, endothelial cells express higher levels of OPG in response to
integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle ...
αvβ3 ligation and the stimulation of NF-kB signalling. OPG expression has been found to promote tumour growth and survival through driving tumour vascularisation and inhibiting TRAIL-induced apoptosis. OPG has been identified as one of the many pro-angiogenic factors involved in the vascularisation of tumours. Tumour
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splittin ...
is required for tumour growth and movement as it supplies the tumour with nutrients and allows metastatic cells to enter the bloodstream. As a decoy receptor for TRAIL, OPG also promotes tumour cell survival by inhibiting TRAIL-induced apoptosis of tumour cells.


Bone metastasis

Bone is a common site of metastasis in cancers such as breast, prostate and lung cancer. In osteolytic bone metastases, tumour cells migrate to the bone and release cytokines such as
parathyroid hormone-related protein Parathyroid hormone-related protein (PTHrP) is a proteinaceous hormone and a member of the parathyroid hormone family secreted by mesenchymal stem cells. It is occasionally secreted by cancer cells (for example, breast cancer, certain types of ...
(PTHrP), IL-8 and PGE2. These cytokines act on osteoblasts to increase RANKL and decrease OPG expression resulting in excess bone resorption. During resorption osteoclasts release nutrients such as growth factors and calcium from the mineralised bone matrix which cultivates a supportive environment for the proliferation and survival of tumour cells. Most bone metastases result in osteolytic lesions, however prostate cancer causes osteoblastic lesions characterised by excess bone formation and high bone density. Prostate cancer releases cytokines such as
insulin-like growth factor The insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system (often referred to as the IGF " ...
(IGF),
endothelin-1 Endothelin 1 (ET-1), also known as preproendothelin-1 (PPET1), is a potent vasoconstrictor peptide produced by vascular endothelial cells. The protein encoded by this gene ''EDN1'' is proteolytically processed to release endothelin 1. Endotheli ...
,
bone morphogenetic proteins Bone morphogenetic proteins (BMPs) are a group of growth factors also known as cytokines and as metabologens. Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of p ...
(BMPs), sclerostin and Wnt proteins that act on local bone to increase osteoblast proliferation and activity. Wnt proteins also act on osteoblasts to upregulate OPG expression through β-catenin signalling and suppress osteoclastic bone resorption.


Multiple myeloma

Multiple myeloma is a type of cancer involving malignant plasma cells, called myeloma cells, within the bone marrow. Multiple myeloma is associated with osteolytic bone lesions as the usually high levels of OPG in the bone marrow are diminished resulting in increased osteoclastic absorption. The reduced OPG in multiple myeloma is caused by suppression of both constitutive OPG transcription and the OPG inducing cytokines TGF-β and Wnt. In addition, the efficacy of OPG in bone marrow is impeded with multiple myeloma by excessive binding to
syndecan-1 Syndecan 1 is a protein which in humans is encoded by the ''SDC1'' gene. The protein is a transmembrane (type I) heparan sulfate proteoglycan and is a member of the syndecan proteoglycan family. The syndecan-1 protein functions as an integral ...
. OPG binds to syndecan-1 on the surface of normal and multiple myeloma plasma cells to be internalised and degraded. However the overabundance of proliferating myeloma cells results in the excessive binding and inhibition of OPG by syndecan-1. Simultaneously, multiple myeloma is associated with unusually high levels of osteoclastogenesis-inducing factors. The decreased OPG transcription and increased OPG protein degradation combined with increased osteoclastogenesis result in the osteolytic lesions that are characteristic of multiple myeloma.


Otosclerosis

Otosclerosis Otosclerosis is a condition of the middle ear where portions of the dense enchondral layer of the bony labyrinth remodel into one or more lesions of irregularly-laid spongy bone. As the lesions reach the stapes the bone is resorbed, then har ...
is a disorder of the middle ear, characterized by abnormal bone growth at the foot plate of the
stapes The ''stapes'' or stirrup is a bone in the middle ear of humans and other animals which is involved in the conduction of sound vibrations to the inner ear. This bone is connected to the oval window by its annular ligament, which allows the foo ...
which affect its mobility, resulting in progressive hearing loss. OPG gene polymorphisms c.9C>G and c.30+15C> have shown genetic association with OTSC in Indian and Tunisian populations. Some of the reports have shown significantly reduced or missing OPG expression in otosclerotic tissues which might be a causal factor for abnormal bone remodeling during disease manifestation.


Juvenile Paget's disease

This is a rare autosomal recessive disease that is associated with mutations in this gene.


References


External links

* * * {{Cytokine receptor modulators TNF receptor family