Osteoprotegerin

Template:Short description Template:Infobox gene 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 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).<ref name="Simonet 1997">Template:Cite journal</ref> OPG also binds to TNF-related apoptosis-inducing ligand (TRAIL) and inhibits TRAIL induced apoptosis of specific cells, including tumour cells.<ref name="Reid 2009">Template:Cite journal</ref> Other OPG ligands include syndecan-1, glycosaminoglycans, von Willebrand factor, and factor VIII-von Willebrand factor complex.<ref name="Baud'huin 2013">Template:Cite journal</ref>

OPG has been identified as having a role in tumour growth and metastasis,<ref name="Reid 2009"/> heart disease,<ref name="Lei 2013">Template:Cite journal</ref><ref name="Hosbond 2012">Template:Cite journal</ref><ref name="Bernardi 2016">Template:Cite journal</ref> immune system development and signalling,<ref name="Baud'huin 2013"/> mental health,<ref name="Hope 2010">Template:Cite journal</ref> diabetes,<ref name="Nabipour 2010">Template:Cite journal</ref> and the prevention of pre-eclampsia<ref name="Shen 2012">Template:Cite journal</ref> and osteoporosis during pregnancy.<ref name="Yano 2001">Template:Cite journal</ref>

Biochemistry

OPG is largely expressed by osteoblast lineage cells of bone, epithelial cells of the gastrointestinal tract, lung, breast and skin,<ref name="Baud'huin 2013"/><ref name="Fortner 2017">Template:Cite journal</ref> vascular endothelial cells,<ref name="Sordillo 2003">Template:Cite journal</ref> as well as B-cells and dendritic cells in the immune system.<ref name="Sordillo 2003"/>

OPG is a soluble glycoprotein which can be found as either a 60-kDa monomer or a 120-kDa dimer linked by disulfide bonds.<ref name="Schneeweis 2005"/> 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).<ref name="Schneeweis 2005">Template:Cite journal</ref> 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.<ref name="Baud'huin 2013"/> Domains 1-4 are cysteine-rich N-terminal domains that interact with RANKL during binding.<ref name="Schneeweis 2005"/> Domains 5-6 are death domains that contribute to the dimerisation of OPG.<ref name="Schneeweis 2005"/> 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.<ref name="Schneeweis 2005"/><ref name="Baud'huin 2013"/>

OPG expression can be upregulated by IL-1β,<ref name="Jurado 2010">Template:Cite journal</ref><ref name="Chung 2017">Template:Cite journal</ref> 1α,25(OH)₂D₃,<ref name="Jurado 2010"/> Wnt/β-catenin signalling through Wnt16, Wnt4 and Wnt3a<ref name="Kobayashi 2015">Template:Cite journal</ref> TNFα<ref name="Reid 2009"/> and estrogen.<ref name="Millan 2015">Template:Cite journal</ref> OPG expression can also be upregulated transcriptionally through DNA binding sites for estrogen receptor α (ER-α)<ref name="Millan 2015"/> and TCF<ref name="Bilezikian 2008">Template:Cite book</ref> in the promoter region of the OPG gene. Downregulation of OPG can be effected by TGF-β1,<ref name="Jurado 2010"/> PTH<ref name="Szulc 2001">Template:Cite journal</ref> and DNA methylation of a CpG island in the OPG gene.<ref name="Delgado-Calle 2012">Template:Cite journal</ref>

Estrogen and OPG regulation

OPG expression in osteoblast lineage cells is highly regulated by estrogens such as estradiol (E2).<ref name="Millan 2015"/><ref name="Michael 2005">Template:Cite journal</ref> E2 transcriptionally regulates OPG expression through binding estrogen receptors (predominantly ER-α) on osteoblast lineage cell surfaces.<ref name="Millan 2015"/> 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.<ref name="Millan 2015"/>

Estrogens can also post-transcriptionally regulate OPG protein expression through the suppression of the microRNA (miRNA) miR-145.<ref name="Jia 2017">Template:Cite journal</ref> miR-145 binds miRNA binding sites in the 3’UTR of OPG mRNA transcripts and suppresses the translation of OPG proteins.<ref name="Jia 2017"/> Estrogen binds its ER-β receptor on the cell surface to suppress many miRNAs, including miR-145,<ref name="Piperigkoua 2017">Template:Cite journal</ref> thus blocking inhibition of OPG mRNA translation.<ref name="Cohen 2017">Template:Cite journal</ref>

Estrogen suppresses osteoclastogenesis through the upregulation of OPG expression in osteoblast lineage cells.<ref name="Michael 2005"/> 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.<ref name="Michael 2005"/> Further, in the absence of aromatase enzymes converting testosterone into estrogen, testosterone and DHT downregulate OPG mRNA expression.<ref name="Hofbauer 2002">Template:Cite journal</ref><ref name="Khosla 2002">Template:Cite journal</ref>

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.<ref name="Simonet 1997"/> 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.<ref name="Bernardi 2016"/>

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.<ref name="Boyce 2008">Template:Cite journal</ref> RANKL is released by osteoblast lineage cells and binds to receptor RANK on the surface of osteoclast progenitor cells<ref name="Boyle 2003">Template:Cite journal</ref> 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).<ref name="Boyce 2015">Template:Cite journal</ref> NFATc1 is a master regulator for the expression of essential cytokines during the differentiation of osteoclast precursor cells into mature osteoclasts, known as osteoclastogenesis.<ref>Template:Cite journal</ref> Mature osteoclasts then bind to bone through tight junctions and release digestive enzymes to resorb the old bone.<ref name="Boyle 2003"/> 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.<ref name="Boyce 2008"/> As a decoy receptor for RANKL, OPG inhibits RANK-RANKL interactions thus suppressing osteoclastogenesis and bone resorption.<ref name="Boyle 2003"/>

OPG is also a decoy receptor for TRAIL, another regulator of osteoclastogenesis in osteoclast precursor cells <ref name="Yen 2012">Template:Cite journal</ref> and an autocrine signal for mature osteoclast cell death.<ref name="Chamoux 2008">Template:Cite journal</ref> 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.<ref name="Chamoux 2008"/> During osteoclastogenesis the different TRAIL receptors on the cell surface change resulting in an increase of apoptosis inducing TRAIL receptors expressed on mature osteoclasts.<ref name="Colucci 2007">Template:Cite journal</ref> 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<ref name="Vitovski 2007">Template:Cite journal</ref> suggesting that it is equally effective at blocking 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 is a bone-related disease caused by increased rates of bone resorption compared to bone formation.<ref name="Snyman 2014">Template:Cite journal</ref> 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.<ref name="Snyman 2014"/>

Osteoporosis is often triggered in post-menopausal women due to reduced estrogen levels associated with the depletion of hormone-releasing ovarian follicles.<ref name="Nelson 2008">Template:Cite journal</ref> 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.<ref name="Millan 2015"/><ref name="Jia 2017"/> Decreased estrogen is a common cause of osteoporosis that can be seen in other conditions such as ovariectomy, ovarian failure, anorexia, and hyperprolactinaemia.<ref name="Meczekalski 2010">Template:Cite journal</ref>

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.<ref name="Bradford 2010">Template:Cite journal</ref> 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.<ref name="Reid 2009"/> When in contact with tumour cells, endothelial cells express higher levels of OPG in response to integrin α_vβ₃ ligation and the stimulation of NF-kB signalling.<ref name="Reid 2009"/>

OPG expression has been found to promote tumour growth and survival through driving tumour vascularisation and inhibiting TRAIL-induced apoptosis.<ref name="Reid 2009"/>

OPG has been identified as one of the many pro-angiogenic factors involved in the vascularisation of tumours.<ref name="Reid 2009"/> Tumour angiogenesis is required for tumour growth and movement as it supplies the tumour with nutrients and allows metastatic cells to enter the bloodstream.<ref name="Reid 2009"/> As a decoy receptor for TRAIL, OPG also promotes tumour cell survival by inhibiting TRAIL-induced apoptosis of tumour cells.<ref name="Reid 2009"/>

Bone metastasis

Bone is a common site of metastasis in cancers such as breast, prostate and lung cancer.<ref name="Dougall 2011">Template:Cite journal</ref> In osteolytic bone metastases, tumour cells migrate to the bone and release cytokines such as parathyroid hormone-related protein (PTHrP), IL-8 and PGE2.<ref name="Bertoldo 2017">Template:Cite book</ref> These cytokines act on osteoblasts to increase RANKL and decrease OPG expression resulting in excess bone resorption.<ref name="Bertoldo 2017"/> 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.<ref name="Dougall 2011"/>

Most bone metastases result in osteolytic lesions, however prostate cancer causes osteoblastic lesions characterised by excess bone formation and high bone density.<ref name="Bertoldo 2017"/> 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.<ref name="Bertoldo 2017"/> Wnt proteins also act on osteoblasts to upregulate OPG expression through β-catenin signalling and suppress osteoclastic bone resorption.<ref name="Bertoldo 2017"/>

Multiple myeloma

Multiple myeloma is a type of cancer involving malignant plasma cells, called myeloma cells, within the bone marrow.<ref name="Palumbo 2011">Template:Cite journal</ref> 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.<ref name="Sordillo 2003"/> The reduced OPG in multiple myeloma is caused by suppression of both constitutive OPG transcription and the OPG inducing cytokines TGF-β<ref name="Sordillo 2003"/> and Wnt.<ref name="Palumbo 2011"/> In addition, the efficacy of OPG in bone marrow is impeded with multiple myeloma by excessive binding to syndecan-1.<ref name="Sordillo 2003"/> OPG binds to syndecan-1 on the surface of normal and multiple myeloma plasma cells to be internalised and degraded.<ref name="Renema 2016">Template:Cite journal</ref><ref name="Standal 2002">Template:Cite journal</ref> However the overabundance of proliferating myeloma cells results in the excessive binding and inhibition of OPG by syndecan-1.<ref name="Standal 2002"/> Simultaneously, multiple myeloma is associated with unusually high levels of osteoclastogenesis-inducing factors.<ref name="Sordillo 2003"/> 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 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 a causal factor for abnormal bone remodeling during disease manifestation. <ref name="Priyadarshi2015">Template:Cite journal</ref>

Juvenile Paget's disease

This is a rare autosomal recessive disease that is associated with mutations in this gene.<ref name=Naot2019>Template:Cite journal</ref>

External links

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