3URF
37-405: 4982 18383 ENSG00000164761 ENSMUSG00000063727 O00300 O08712 NM_002546 NM_008764 NP_002537 NP_032790 Osteoprotegerin ( OPG ), also known as osteoclastogenesis inhibitory factor ( OCIF ) or tumour necrosis factor receptor superfamily member 11B ( TNFRSF11B ), is a cytokine receptor of the tumour necrosis factor (TNF) receptor superfamily encoded by
74-458: A causal factor for abnormal bone remodeling during disease manifestation. This is a rare autosomal recessive disease that is associated with mutations in this gene. 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 because
111-430: A classification, though seemingly cumbersome, provides several unique perspectives for attractive pharmacotherapeutic targets.) Cytokine receptors may be both membrane-bound and soluble. Soluble cytokine receptors are extremely common regulators of cytokine function. Soluble cytokine receptors typically consist of the extracellular portions of membrane-bound receptors. . This membrane protein –related article
148-522: 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 signalling, activating NF-κB signalling and upregulating NFATc1 expression. During osteoclastogenesis
185-487: A deficiency of cytokine receptors has now been directly linked to certain debilitating immunodeficiency states. In this regard, and also because the redundancy and pleiotropy of cytokines are a consequence of their homologous receptors, many authorities are now of the opinion that a classification of cytokine receptors would be more clinically and experimentally useful. A classification of cytokine receptors based on their three-dimensional structure has been attempted. (Such
222-525: A male-producing temperature, the organism will develop female and conversely, if exposed to less aromatase at female-producing temperatures, the organism will develop male (see sex reversal ). In organisms that develop through genetic sex determination, temperature does not affect aromatase expression and function, suggesting that aromatase is the target molecule for temperature during TSD (for challenges to this argument, see temperature-dependent sex determination ). It varies from species to species whether it
259-674: A mutation of gene CYP19 and inherited in an autosomal recessive way. Accumulations of androgens during pregnancy may lead to virilization of a female at birth (males are not affected). Females will have primary amenorrhea . Individuals of both sexes will be tall, as lack of estrogen does not bring the epiphyseal lines to closure. The inhibition of aromatase can cause hypoestrogenism (low estrogen levels). The following natural products have been found to have inhibiting effects on aromatase. Extracts of certain (white button variety: Agaricus bisporus ) mushrooms have been shown to inhibit aromatase in vitro . Aromatase inhibitors , which stop
296-657: A number of alternative non-coding first exons that regulate tissue specific expression. CYP19 is present in an early-diverging chordate , the cephalochordate amphioxus (the Florida lancelet , Branchiostoma floridae ), but not in the earlier diverging tunicate Ciona intestinalis . Thus, the aromatase gene evolved early in chordate evolution and does not appear to be present in nonchordate invertebrates (e.g. insects , molluscs , echinoderms , sponges , corals ). However, estrogens may be synthesized in some of these organisms, via other unknown pathways. Aromatase activity
333-407: A role in tumour growth and metastasis, heart disease, immune system development and signalling, mental health, diabetes, and the prevention of pre-eclampsia and osteoporosis during pregnancy. OPG is largely expressed by osteoblast lineage cells of bone, epithelial cells of the gastrointestinal tract, lung, breast and skin, vascular endothelial cells, as well as B-cells and dendritic cells in
370-743: Is a stub . You can help Misplaced Pages by expanding it . This article about a biochemical receptor is a stub . You can help Misplaced Pages by expanding it . Aromatase 3EQM , 3S79 , 3S7S , 4GL5 , 4GL7 , 4KQ8 1588 13075 ENSG00000137869 ENSMUSG00000032274 P11511 P28649 NM_001347252 NM_001347253 NM_001347254 NM_001347255 NM_001347256 NM_031226 NM_007810 NM_001348171 NM_001348172 NM_001348173 NP_001334181 NP_001334182 NP_001334183 NP_001334184 NP_001334185 NP_112503 NP_001335100 NP_001335101 NP_001335102 NP_031836 Aromatase ( EC 1.14.14.14 ), also called estrogen synthetase or estrogen synthase ,
407-735: 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 . The higher rate of bone resorption compared to bone formation leads to the increased porosity and low bone mineral density of individuals with osteoporosis. 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 α v β 3 ligation and
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#1732859252773444-444: 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
481-462: 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
518-480: 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,
555-417: Is also susceptible to environmental influences, particularly temperature. In species with temperature-dependent sex determination , aromatase is expressed in higher quantities at temperatures that yield female offspring. Despite the fact that data suggest temperature controls aromatase quantities, other studies have shown that aromatase can overpower the effects of temperature: if exposed to more aromatase at
592-601: 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 reactions involved in steroidogenesis . In particular, aromatase is responsible for the aromatization of androgens into estrogens . The enzyme aromatase can be found in many tissues including gonads ( granulosa cells ), brain , adipose tissue , placenta , blood vessels , skin , and bone , as well as in tissue of endometriosis , uterine fibroids , breast cancer , and endometrial cancer . It
629-454: Is an important factor in sexual development . Aromatase is localized in the endoplasmic reticulum where it is regulated by tissue-specific promoters that are in turn controlled by hormones , cytokines , and other factors. It catalyzes the last steps of estrogen biosynthesis from androgens (specifically, it transforms androstenedione to estrone and testosterone to estradiol ). These steps include three successive hydroxylations of
666-452: Is due to mutations in the CYP19A1 gene which encodes aromatase. It is inherited in an autosomal dominant fashion. It has been suggested that the pharaoh Akhenaten and other members of his family may have had from this disorder, but more recent genetic tests suggest otherwise. It is one of the causes of familial precocious puberty—a condition first described in 1937. This syndrome is due to
703-432: Is increased by age , obesity , insulin , gonadotropins , and alcohol . It also appears to be enhanced in certain estrogen-dependent local tissue next to breast tissue, endometrial cancer , endometriosis , and uterine fibroids . Aromatase activity is decreased or antagonized by prolactin , anti-Müllerian hormone and glyphosate . Aromatase is generally highly present during the differentiation of ovaries. It
740-401: 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
777-557: Is the aromatase protein that has different activity at different temperatures or whether the amount of transcription undergone by the aromatase gene is what is temperature-sensitive, but in either case, differential development is observed at different temperatures. Aromatase in the brain is usually only expressed in neurons . However, following penetrative brain injury of both mice and zebra finches , it has been shown to be expressed in astrocytes . It has also been shown to decrease apoptosis following brain injury in zebra finches. This
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#1732859252773814-598: Is thought to be due to the neuroprotective actions of estrogens, including estradiol. Research has found that two pro-inflammatory cytokines , interleukin-1β (IL-1β) and interleukin-6 (IL-6), are responsible for the induction of aromatase expression in astrocytes following penetrative brain injury in the zebra finch. A number of investigators have reported on a rather rare syndrome of excess aromatase activity. In boys, it creates gynecomastia , and in girls, precocious puberty and gigantomastia . In both sexes, early epiphyseal closure leads to short stature. This condition
851-623: 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 ). OPG also binds to TNF-related apoptosis-inducing ligand ( TRAIL ) and inhibits TRAIL induced apoptosis of specific cells, including tumour cells. Other OPG ligands include syndecan-1 , glycosaminoglycans , von Willebrand factor , and factor VIII -von Willebrand factor complex. OPG has been identified as having
888-513: The 19-methyl group of androgens, followed by simultaneous elimination of the methyl group as formate and aromatization of the A-ring. Aromatase is expressed in the gonads , placenta , brain , adipose tissue , bone , and other tissues . It is almost undetectable in adult human liver . The gene expresses two transcript variants. In humans, the gene CYP19, located on chromosome 15q 21.1, encodes aromatase. The gene has nine coding exons and
925-542: The absence of aromatase enzymes converting testosterone into estrogen, testosterone and DHT downregulate OPG mRNA expression. 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. The RANK/RANKL/OPG axis
962-598: The bloodstream. As a decoy receptor for TRAIL, OPG also promotes tumour cell survival by inhibiting TRAIL-induced apoptosis of tumour cells. 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 (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
999-429: 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 (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
1036-444: 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
1073-600: 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 blocking osteoclastogenesis and inhibiting osteoclast apoptosis. A normal steady state of bone metabolism seems to be present in patients with atrophic nonunion fractures, despite
1110-435: 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) 2 D 3 , 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
1147-585: The efficacy of OPG in bone marrow is impeded with multiple myeloma by excessive binding to syndecan-1 . 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
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1184-424: The high serum OPG. Only serum OPG was significantly higher in the patients compared to healed and healing controls. (49) Osteoporosis 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
1221-683: 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 K D of 3 μM 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 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
1258-684: 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 (IGF), endothelin-1 , bone morphogenetic proteins (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
1295-549: The osteolytic lesions that are characteristic of multiple myeloma. Otosclerosis is a disorder of the middle ear, characterized by abnormal bone growth at the foot plate of the stapes 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
1332-432: 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. OPG expression in osteoblast lineage cells is highly regulated by estrogens such as estradiol (E2). E2 transcriptionally regulates OPG expression through binding estrogen receptors (predominantly ER-α) on osteoblast lineage cell surfaces. The E2-ERα complex then translocates into
1369-440: 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 is required for tumour growth and movement as it supplies the tumour with nutrients and allows metastatic cells to enter
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