View source for RANKL

{{Short description|Mammalian protein found in Homo sapiens}}
{{redirect|TRANCE||Trance (disambiguation)}}
{{distinguish|text=[[RANK]], the osteoclast cell-surface receptor that binds to RANKL}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox gene}}
'''Receptor activator of nuclear factor kappa-{{Script|Grek|Β}} ligand''' ('''RANKL'''), also known as '''tumor necrosis factor ligand superfamily member 11''' ('''TNFSF11'''), '''TNF-related activation-induced cytokine''' ('''TRANCE'''), '''osteoprotegerin ligand''' ('''OPGL'''), and '''osteoclast differentiation factor''' ('''ODF'''), is a [[protein]] that in humans is encoded by the ''TNFSF11'' [[gene]].<ref name="pmid9312132">{{cite journal | vauthors = Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS, Frankel WN, Lee SY, Choi Y | title = TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells | journal = The Journal of Biological Chemistry | volume = 272 | issue = 40 | pages = 25190–25194 | date = October 1997 | pmid = 9312132 | doi = 10.1074/jbc.272.40.25190 | doi-access = free }}</ref><ref name="pmid9367155">{{cite journal | vauthors = Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L | title = A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function | journal = Nature | volume = 390 | issue = 6656 | pages = 175–179 | date = November 1997 | pmid = 9367155 | doi = 10.1038/36593 | s2cid = 4373990 | bibcode = 1997Natur.390..175A }}</ref>

RANKL is known as a type II [[membrane protein]] and is a member of the [[tumor necrosis factor]] (TNF) superfamily.<ref name="pmid21445556">{{cite journal | vauthors = Hanada R, Hanada T, Sigl V, Schramek D, Penninger JM | title = RANKL/RANK-beyond bones | journal = Journal of Molecular Medicine | volume = 89 | issue = 7 | pages = 647–656 | date = July 2011 | pmid = 21445556 | doi = 10.1007/s00109-011-0749-z | s2cid = 25285776 }}</ref>  RANKL has been identified to affect the [[immune system]] and control bone regeneration and remodeling. RANKL is an [[apoptosis]] regulator gene, a binding partner of [[osteoprotegerin]] (OPG), a [[Ligand (biochemistry)|ligand]] for the receptor [[RANK]] and controls cell proliferation by modifying protein levels of [[ID4|Id4]], [[ID2|Id2]] and [[cyclin D1]].<ref name="pmid22969763">{{cite journal | vauthors = Mueller CG, Hess E | title = Emerging Functions of RANKL in Lymphoid Tissues | journal = Frontiers in Immunology | volume = 3 | pages = 261 | year = 2012 | pmid = 22969763 | pmc = 3432452 | doi = 10.3389/fimmu.2012.00261 | doi-access = free }}</ref><ref name="Wada_2006">{{cite journal | vauthors = Wada T, Nakashima T, Hiroshi N, Penninger JM | title = RANKL-RANK signaling in osteoclastogenesis and bone disease | journal = Trends in Molecular Medicine | volume = 12 | issue = 1 | pages = 17–25 | date = January 2006 | pmid = 16356770 | doi = 10.1016/j.molmed.2005.11.007 }}</ref> RANKL is expressed in several tissues and organs including: skeletal muscle, thymus, liver, colon, small intestine, adrenal gland, osteoblast, mammary gland epithelial cells, prostate and pancreas.<ref name="Wada_2006"/> Variation in concentration levels of RANKL throughout several organs reconfirms the importance of RANKL in tissue growth (particularly bone growth) and immune functions within the body.

== Tissue expression ==
The level of RANKL expression does not linearly correlate to the effect of this ligand. High protein expression of RANKL is commonly detected in the [[Lung|lungs]], [[thymus]] and [[Lymph node|lymph nodes]].  Low protein expression is found in [[bone marrow]], the [[stomach]], [[peripheral blood]], the [[spleen]], the [[placenta]], [[leukocytes]], the [[heart]], the [[thyroid]], and [[skeletal muscle]].<ref name="Wada_2006"/> While bone marrow expresses low levels of RANKL, RANKL plays a critical role for adequate bone metabolism. This surface-bound molecule (also known as CD254), found on [[osteoblast]]s, serves to activate [[osteoclast]]s, which are critically involved in [[bone resorption]].  Osteoclastic activity is triggered via the osteoblasts' surface-bound RANKL activating the osteoclasts' surface-bound [[RANK|receptor activator of nuclear factor kappa-B (RANK)]]. Recent studies suggest that in postnatal bones, the [[osteocyte]] is the major source of RANKL regulating bone remodeling.<ref name="Robling">{{cite journal | vauthors = Robling AG, Bonewald LF | title = The Osteocyte: New Insights | journal = Annual Review of Physiology | volume = 82 | issue = 1 | pages = 485–506 | date = February 2020 | pmid = 32040934 | pmc = 8274561 | doi = 10.1146/annurev-physiol-021119-034332 | hdl = 1805/30982 }}</ref><ref>{{cite journal | vauthors = Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'Brien CA | title = Matrix-embedded cells control osteoclast formation | journal = Nature Medicine | volume = 17 | issue = 10 | pages = 1235–1241 | date = September 2011 | pmid = 21909103 | pmc = 3192296 | doi = 10.1038/nm.2448 }}</ref><ref>{{cite journal | vauthors = Xiong J, Piemontese M, Onal M, Campbell J, Goellner JJ, Dusevich V, Bonewald L, Manolagas SC, O'Brien CA | title = Osteocytes, not Osteoblasts or Lining Cells, are the Main Source of the RANKL Required for Osteoclast Formation in Remodeling Bone | journal = PLOS ONE | volume = 10 | issue = 9 | pages = e0138189 | date = 2015-01-01 | pmid = 26393791 | pmc = 4578942 | doi = 10.1371/journal.pone.0138189 | doi-access = free | bibcode = 2015PLoSO..1038189X }}</ref><ref>{{cite journal | vauthors = Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, Penninger JM, Takayanagi H | title = Evidence for osteocyte regulation of bone homeostasis through RANKL expression | journal = Nature Medicine | volume = 17 | issue = 10 | pages = 1231–1234 | date = September 2011 | pmid = 21909105 | doi = 10.1038/nm.2452 | s2cid = 21188945 }}</ref> RANKL derived from other cell types contributes to bone loss in conditions involving [[inflammation]] such as [[rheumatoid arthritis]], and in [[Lytic lesion|lytic lesions]] caused by [[cancer]], such as in [[multiple myeloma]].

== Gene and expression ==
RANKL can be expressed in three different molecular forms consisting of either a: (1) trimeric transmembrane protein, (2) primary secreted form, and (3) truncated [[ectodomain]].<ref name="pmid21850548">{{cite journal | vauthors = Findlay DM, Atkins GJ | title = Relationship between serum RANKL and RANKL in bone | journal = Osteoporosis International | volume = 22 | issue = 10 | pages = 2597–2602 | date = October 2011 | pmid = 21850548 | doi = 10.1007/s00198-011-1740-9 | s2cid = 908214 }}</ref> RANKL is identified as a part of the TNF family; RANKL is specifically categorized under the TNFSF11, the TNF ligand superfamily member. RANKL is composed of 314 amino acids and was originally described to have a gene sequence containing 5 [[exons]].<ref name="Walsh_2013">{{cite journal | vauthors = Walsh NC, Alexander KA, Manning CA, Karmakar S, Wang JF, Weyand CM, Pettit AR, Gravallese EM | title = Activated human T cells express alternative mRNA transcripts encoding a secreted form of RANKL | journal = Genes and Immunity | volume = 14 | issue = 5 | pages = 336–345 | year = 2013 | pmid = 23698708 | pmc = 3740552 | doi = 10.1038/gene.2013.29 }}</ref><ref name="O'Brien_2010">{{cite journal | vauthors = O'Brien CA | title = Control of RANKL gene expression | journal = Bone | volume = 46 | issue = 4 | pages = 911–919 | date = April 2010 | pmid = 19716455 | pmc = 2842447 | doi = 10.1016/j.bone.2009.08.050 }}</ref> Among the exons, Exon 1 encoded the intracellular and transmembrane protein domains and Exon 2-5 encoded the extracellular domains.<ref name="Walsh_2013"/> RANKL’s extracellular domains are similar to other TNF family members in regards to the structural homology and are able to cleave from the cell surface.<ref name="Walsh_2013"/> While the function and significance of A kinase anchor protein 11([[AKAP11]]) is presently unknown, AKAP11 is immediately upstream from RANKL for all species that has a RANKL gene.<ref name="O'Brien_2010"/> The upstream of AKAP11 may suggest there is a complex regulator process that regulates the level of RANKL expression.

== Function ==
RANKL is a member of the [[tumor necrosis factor]] (TNF) [[cytokine]] family. It binds to RANK on cells of the myeloid lineage and functions as a key factor for [[osteoclast]] differentiation and activation. RANKL may also bind to [[osteoprotegerin]], a protein secreted mainly by cells of the osteoblast lineage which is a potent inhibitor of osteoclast formation by preventing binding of RANKL to RANK.  RANKL also has a function in the immune system, where it is expressed by [[T helper cell]]s and is thought to be involved in [[dendritic cell]] maturation.  It is a [[dendritic cell]] survival factor and helps regulate [[T cell]]-dependent immune responses. T cell activation induces RANKL expression and can lead to an increase of osteoclastogenesis and bone loss. RANKL can also activate the antiapoptotic kinase [[AKT|AKT/PKB]] through a signaling complex involving [[Src (gene)|SRC kinase]] and tumor necrosis factor receptor-associated factor 6 ([[TRAF6]]), indicating that RANKL may have a role in the regulation of [[apoptosis]].<ref name = "entrez">{{cite web | title = Entrez Gene: TNFSF11 tumor necrosis factor (ligand) superfamily, member 11| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8600}}</ref>  A further role for RANKL in immunity was found in sinusoidal [[macrophage]]s in lymph nodes that alert the immune system to lymph-borne [[antigen]]s.<ref name=Camara>{{cite journal | vauthors = Camara A, Cordeiro OG, Alloush F, Sponsel J, Chypre M, Onder L, Asano K, Tanaka M, Yagita H, Ludewig B, Flacher V, Mueller CG | title = Lymph Node Mesenchymal and Endothelial Stromal Cells Cooperate via the RANK-RANKL Cytokine Axis to Shape the Sinusoidal Macrophage Niche | journal = Immunity | volume = 50 | issue = 6 | pages = 1467–1481.e6 | date = June 2019 | pmid = 31201093 | doi = 10.1016/j.immuni.2019.05.008 | doi-access = free }}</ref> In addition to directly signaling through RANK for macrophage differentiation, RANKL activates the adjacent [[lymphatic endothelium|lymphatic endothelial]] cells to create a niche environment for these specialized immune cells.<ref name=Camara/>

== Animal models ==
Targeted disruption of the related gene in mice led to severe [[osteopetrosis]] and a lack of osteoclasts. Deficient mice, with an inactivation of RANKL or its receptor RANK, exhibited defects in early differentiation of T and B lymphocytes, and failed to form [[Mammary gland#Structure|lobulo-alveolar mammary structures]] during pregnancy.<ref name="Wada_2006"/><ref name = "entrez"/>
It was observed that during pregnancy, RANK-RANKL signaling played a critical role in regulating skeletal calcium release; in which contributed to the hormone response that stimulated proliferation in the mammary cells.<ref name="Wada_2006"/> Ultimately, impaired lobuloalveolar mammary structures resulted in death of the fetus.<ref name="Wada_2006"/> Those who suffer from osteoporosis often have a cardiovascular defect, such as heart failure. Some studies suggest, since RANK-RANKL pathway regulates calcium release and homeostasis, RANK-RANKL signal could invertedly affect the cardiovascular system; thus, an explanation for the positive correlation between osteoporosis and cardiovascular deficiencies.<ref name="Wada_2006"/>

== Role in cancer ==
[[Primary tumor|Primary tumors]] will commonly metastasize into the bone. Breast and prostate cancers typically have a greater chance of inducing [[Secondary cancer|secondary cancers]] within bone.<ref name="pmid11417967">{{cite journal | vauthors = Coleman RE | title = Metastatic bone disease: clinical features, pathophysiology and treatment strategies | journal = Cancer Treatment Reviews | volume = 27 | issue = 3 | pages = 165–176 | date = June 2001 | pmid = 11417967 | doi = 10.1053/ctrv.2000.0210 }}</ref> [[Stephen Paget]]'s [[seed and soil theory]] suggests, the microenvironment in bone creates a sufficient ‘soil’ for secondary tumors to grow in. Some studies suggest the expression of RANKL allows sufficient micro environmental conditions to influence cancer cell migration (i.e. [[chronic lymphocytic leukemia]] (CLL) and [[multiple myeloma]]).<ref name=pmid23139212 /> Among patients with multiple myeloma, RANKL activity was greatly increased. In fact RANKL surface expression and secreted RANKL expression was reported to be increased, 80% and 50% respectively.<ref name="pmid23139212">{{cite journal | vauthors = Schmiedel BJ, Scheible CA, Nuebling T, Kopp HG, Wirths S, Azuma M, Schneider P, Jung G, Grosse-Hovest L, Salih HR | title = RANKL expression, function, and therapeutic targeting in multiple myeloma and chronic lymphocytic leukemia | journal = Cancer Research | volume = 73 | issue = 2 | pages = 683–694 | date = January 2013 | pmid = 23139212 | doi = 10.1158/0008-5472.CAN-12-2280 | doi-access = free }}</ref> Therefore, RANKL is considered to be a key signal regulator for cancer-induced bone loss.

After secondary tumors cells have migrated to bone, the tumor cell will secrete cytokines and growth factors that can act on osteoblast lineage cells. Since osteoblasts control the regulation of RANKL, the stimulation via cytokines and growth factors will then stimulate osteoblasts to increase the expression of RANKL, often while simultaneously reducing bone formation. The additional RANKL-mediated osteoclast frequency and activity will in turn increase secretion of growth factors, or matrix derived factors, which can ultimately increase tumor growth and bone destruction activity.{{Fact|date=November 2024}}

== Clinical significance ==
RANKL, through its ability to stimulate osteoclast formation and activity, is a critical mediator of bone resorption and overall bone density. Overproduction of RANKL is implicated in a variety of degenerative bone diseases, such as [[rheumatoid arthritis]] and [[psoriatic arthritis]]. In addition to degenerative bone diseases, bone metastases can also induce pain and other abnormal health complexities that can significantly reduce a cancer patient’s quality of life. Some examples of these complications that are a consequence of bone metastasis are: hypercalcemia, pathological fractures and spinal cord compression.<ref name="Castellano_2011">{{cite journal | vauthors = Castellano D, Sepulveda JM, García-Escobar I, Rodriguez-Antolín A, Sundlöv A, Cortes-Funes H | title = The role of RANK-ligand inhibition in cancer: the story of denosumab | journal = The Oncologist | volume = 16 | issue = 2 | pages = 136–145 | year = 2011 | pmid = 21285392 | pmc = 3228090 | doi = 10.1634/theoncologist.2010-0154 }}</ref> Some findings also suggest that some cancer cells, particularly prostate cancer cells, can activate an increase in bone remodeling and ultimately increase overall bone production.<ref name="Castellano_2011"/> This increase in bone remodeling and bone production increases the overall growth of bone metastasizes. The overall control of bone remodeling is regulated by the binding of RANKL with its receptor or its decoy receptor, respectively, RANK and OPG.<ref name="Castellano_2011"/>

=== Denosumab ===
{{main article|Denosumab}}
Denosumab is an FDA-approved fully human monoclonal antibody to RANKL and during pre-clinical trials was first used to treat postmenopausal patients suffering with osteoporosis (PMO).<ref name="Castellano_2011"/><ref name="pmid19239825">{{cite journal | vauthors = Miller PD | title = Denosumab: anti-RANKL antibody | journal = Current Osteoporosis Reports | volume = 7 | issue = 1 | pages = 18–22 | date = March 2009 | pmid = 19239825 | doi = 10.1007/s11914-009-0004-5 | s2cid = 10465712 }}</ref> In denosumab's third stage of the FDA's clinical trial, it was shown to: (1) decrease bone turnover, (2) reduce fractures in the PMO population, and (3) increase bone mineral density.<ref name="Castellano_2011"/> The anti-RANKL antibody, denosumab, is also approved for use in cancer settings, and in those indications, it is branded as Xgeva. In both prostate and breast cancer, denosumab has been shown to reduce cancer treatment–induced bone loss.<ref name="Castellano_2011"/>

==== Prostate cancer ====
The HALT-prostate cancer trial (also known as NCT00089674) included 1468 non-metastatic prostate cancer patients who were currently receiving [[androgen deprivation therapy]].<ref name="NCT00089674">{{cite journal | url = http://clinicaltrials.gov/ct2/show/NCT00089674 | journal = Nct00089674 | title = AMG 162 in the Treatment of Bone Loss in Subjects Undergoing Androgen-Deprivation Therapy for Non-metastatic Prostate Cancer | date = 20 September 2018 | publisher = ClinicalTrials.gov }}</ref> Randomly selected patients were given either 60&nbsp;mg of denosumab or calcium and vitamin D supplements. This was done to measure the effectiveness of preventing treatment-induced bone loss.<ref name="Castellano_2011"/> The patients who received 60&nbsp;mg of denosumab showed a +5.6% increased in bone mineral density and a 1.5% decrease in bone fracture rates.<ref name="Castellano_2011"/>

Another clinical trial (NCT00321620) was established to determine the safety and effectiveness of using denosumab compared to [[zoledronic acid]].<ref name="NCT00321620">{{cite journal | url = http://clinicaltrials.gov/ct2/show/NCT00321620 | journal = Nct00321620 | title = Study of Denosumab vs. Zoledronic Acid to Treat Bone Metastases in Men With Hormone-refractory Prostate Cancer | date = August 2018 | publisher = ClinicalTrials.gov }}</ref> In this trial, they used 1901 bone metastatic prostate patients whom were also suffering with other complication of bone diseases. Again, patients were randomized and some were given either 120&nbsp;mg of denosumab or 4&nbsp;mg of zoledronic acid.<ref name="Castellano_2011"/> Patients who were given 120&nbsp;mg of denosumab (in comparison to those who were given 4&nbsp;mg of zoledronic acid) showed a greater increase in hypocalcemia, a greater resistance to bone turnover markers uNTx, a delay response in both pathological fractures and spinal cord compression.<ref name="Castellano_2011"/> However, survival rates for both clinical groups were comparable.<ref name="Castellano_2011"/>

==== Breast cancer ====
Hormone receptor positive breast cancer patients have a significant increased risk of complications such as [[osteopenia]] and [[osteoporosis]]. About two out of every three breast cancer patients are hormone receptor positive.<ref name="cancer org">{{cite web|title=Hormone therapy for breast cancer|url=http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-treating-hormone-therapy|publisher=Cancer.org|access-date=2014-01-31|archive-date=2 December 2016|archive-url=https://web.archive.org/web/20161202154704/http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-treating-hormone-therapy|url-status=dead}}</ref> In the past several years, denosumab has been used in clinical trials, primarily because a large population is affected by bone complication among those who have breast cancer.

252 patients enlisted in the HALT-BC clinical trial (also known as NCT00089661). In addition to receiving vitamin D and calcium supplements, half of the patients were randomly given 60&nbsp;mg of denosumab while the other half were given a placebo.<ref name="Castellano_2011"/><ref name="NCT00089661">{{cite journal | url = http://clinicaltrials.gov/ct2/show/NCT00089661 | journal = Nct00089661 | title = AMG 162 in the Treatment of Bone Loss in Subjects Undergoing Aromatase Inhibitor Therapy for Non-metastatic Breast Cancer | date = 20 September 2018 | publisher = ClinicalTrials.gov }}</ref> Patients given denosumab had an increase in [[Lumbar vertebrae|lumbar spine]] bone mineral density, a decrease in bone turnover markers, with no significant change in survival rates.<ref name="Castellano_2011"/>

NCT00321464 was another phase III [[Randomized controlled trial|RCT]].<ref name="NCT00321464">{{cite journal | url = http://clinicaltrials.gov/ct2/show/NCT00089661 | journal = Nct00321464 | title = A Study Comparing Denosumab vs. Zoledronic Acid for the Treatment of Bone Metastases in Breast Cancer Subjects | date = 20 September 2018 | publisher = ClinicalTrials.gov }}</ref> Similar to NCT00321620 (prostate), this trial measured the safety and efficacy of denosumab versus [[zoledronic acid]]. Both groups showed similar survival rates and adverse event frequency.<ref name="Castellano_2011"/>

==== Multiple myeloma ====
Patients whom are diagnosed with multiple myeloma have approximately 80-100% chance of developing bone complications due to an increase in activity and/or formation of osteoclasts and a decrease activity of osteoblasts.<ref name=pmid23139212 /><ref name="Castellano_2011"/> In a stage II clinical trial, denosumab decreased bone turnover markers by blocking the RANKL/RANK pathway.<ref name="Castellano_2011"/> Once this trial was completed, 1176 patients with either multiple myeloma or progressed cancers were entered into the stage III clinical trial (known as NCT00330759).<ref name="NCT00330759">{{cite journal | url = http://clinicaltrials.gov/ct2/show/NCT00330759 | journal = Nct00330759 | title = Study of Denosumab vs. Zoledronic Acid to Treat Bone Metastases in Subjects With Advanced Cancer or Multiple Myeloma | date = August 2018 | publisher = ClinicalTrials.gov }}</ref> The main objective of the NCT00330759 trial was to compare effects of patients who were given 120&nbsp;mg of denosumab relative to patients give 4&nbsp;mg of zoledronic acid. As a result of this trial, during a month period, patients who received denosumab had a decrease in pathological fractures and spinal cord compression; however, as time progressed it appear that denosumab had significantly delayed bone complications.<ref name="Castellano_2011"/> In both breast and prostate cancers, patients in either denosumab or zoledronic acid groups both appeared to have comparable adverse events and survival rates.<ref name="Castellano_2011"/>

=== Medroxyprogesterone acetate ===
{{main article|Medroxyprogesterone acetate}}
Women with menopause have often been given various types of postmenopausal hormone therapies to prevent osteoporosis and reduce menopausal symptoms.<ref name="Wood_2013">{{cite journal | vauthors = Wood CE, Branstetter D, Jacob AP, Cline JM, Register TC, Rohrbach K, Huang LY, Borgerink H, Dougall WC | title = Progestin effects on cell proliferation pathways in the postmenopausal mammary gland | journal = Breast Cancer Research | volume = 15 | issue = 4 | pages = R62 | year = 2013 | pmid = 23938070 | pmc = 3978455 | doi = 10.1186/bcr3456 | doi-access = free }}</ref> [[Medroxyprogesterone acetate]] (MPA) is a synthetic progestin and was commonly used as a contraceptive or used as a hormone therapy for endometriosis or osteoporosis. Recent studies suggest, using MPA increases patient risks of developing [[breast cancer]] due to an increase expression of RANKL.<ref name="Wood_2013"/> MPA causes a substantial induction of RANKL in mammary-gland epithelial cells while deletion of RANKL decreases the incidence MPA-induced breast cancer. Hence inhibition of RANKL has potential for the prevention and treatment of breast cancer.<ref name="pmid20881962">{{cite journal | vauthors = Schramek D, Leibbrandt A, Sigl V, Kenner L, Pospisilik JA, Lee HJ, Hanada R, Joshi PA, Aliprantis A, Glimcher L, Pasparakis M, Khokha R, Ormandy CJ, Widschwendter M, Schett G, Penninger JM | title = Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer | journal = Nature | volume = 468 | issue = 7320 | pages = 98–102 | date = November 2010 | pmid = 20881962 | pmc = 3084017 | doi = 10.1038/nature09387 | bibcode = 2010Natur.468...98S }}</ref><ref name="pmid20881963">{{cite journal | vauthors = Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, Pinkas J, Branstetter D, Dougall WC | title = RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis | journal = Nature | volume = 468 | issue = 7320 | pages = 103–107 | date = November 2010 | pmid = 20881963 | doi = 10.1038/nature09495 | s2cid = 4322105 | bibcode = 2010Natur.468..103G }}</ref>

== See also ==
* [[Cluster of differentiation]]
* [[RANK]]
* [[Osteoprotegerin]]
* [[Osteoimmunology]]

== References ==
{{reflist|35em}}

== Further reading ==
{{refbegin|35em}}
* {{cite journal | vauthors = Whyte MP | title = The long and the short of bone therapy | journal = The New England Journal of Medicine | volume = 354 | issue = 8 | pages = 860–863 | date = February 2006 | pmid = 16495400 | doi = 10.1056/NEJMe068003 }} [http://content.nejm.org/cgi/content/extract/354/8/860 link]
* {{cite journal | vauthors = Buckley KA, Fraser WD | title = Receptor activator for nuclear factor kappaB ligand and osteoprotegerin: regulators of bone physiology and immune responses/potential therapeutic agents and biochemical markers | journal = Annals of Clinical Biochemistry | volume = 39 | issue = Pt 6 | pages = 551–556 | date = November 2002 | pmid = 12564836 | doi = 10.1258/000456302760413324 }}
* {{cite journal | vauthors = Jeffcoate W | title = Vascular calcification and osteolysis in diabetic neuropathy-is RANK-L the missing link? | journal = Diabetologia | volume = 47 | issue = 9 | pages = 1488–1492 | date = September 2004 | pmid = 15322748 | doi = 10.1007/s00125-004-1477-5 | doi-access = free }}
* {{cite journal | vauthors = Collin-Osdoby P | title = Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin | journal = Circulation Research | volume = 95 | issue = 11 | pages = 1046–1057 | date = November 2004 | pmid = 15564564 | doi = 10.1161/01.RES.0000149165.99974.12 | s2cid = 263573984 | doi-access =  }}
* {{cite journal | vauthors = Whyte MP, Mumm S | title = Heritable disorders of the RANKL/OPG/RANK signaling pathway | journal = Journal of Musculoskeletal & Neuronal Interactions | volume = 4 | issue = 3 | pages = 254–267 | date = September 2004 | pmid = 15615493 }}
* {{cite journal | vauthors = Clohisy DR, Mantyh PW | title = Bone cancer pain and the role of RANKL/OPG | journal = Journal of Musculoskeletal & Neuronal Interactions | volume = 4 | issue = 3 | pages = 293–300 | date = September 2004 | pmid = 15615497 }}
* {{cite journal | vauthors = Anandarajah AP, Schwarz EM | title = Anti-RANKL therapy for inflammatory bone disorders: Mechanisms and potential clinical applications | journal = Journal of Cellular Biochemistry | volume = 97 | issue = 2 | pages = 226–232 | date = February 2006 | pmid = 16240334 | doi = 10.1002/jcb.20674 | s2cid = 33543150 }}
* {{cite journal | vauthors = Baud'huin M, Duplomb L, Ruiz Velasco C, Fortun Y, Heymann D, Padrines M | title = Key roles of the OPG-RANK-RANKL system in bone oncology | journal = Expert Review of Anticancer Therapy | volume = 7 | issue = 2 | pages = 221–232 | date = February 2007 | pmid = 17288531 | doi = 10.1586/14737140.7.2.221 | s2cid = 12283459 }}
* {{cite journal | vauthors = Yogo K, Ishida-Kitagawa N, Takeya T | title = Negative autoregulation of RANKL and c-Src signaling in osteoclasts | journal = Journal of Bone and Mineral Metabolism | volume = 25 | issue = 4 | pages = 205–210 | year = 2007 | pmid = 17593489 | doi = 10.1007/s00774-007-0751-2 | s2cid = 32120753 }}
* {{cite journal | vauthors = Boyce BF, Xing L | title = Biology of RANK, RANKL, and osteoprotegerin | journal = Arthritis Research & Therapy | volume = 9 | issue = Suppl 1 | pages = S1 | year = 2007 | pmid = 17634140 | pmc = 1924516 | doi = 10.1186/ar2165 | doi-access = free }}
* {{cite journal | vauthors = McClung M | title = Role of RANKL inhibition in osteoporosis | journal = Arthritis Research & Therapy | volume = 9 | issue = Suppl 1 | pages = S3 | year = 2007 | pmid = 17634142 | pmc = 1924518 | doi = 10.1186/ar2167 | doi-access = free }}
{{refend}}

== External links ==
* [https://web.archive.org/web/20061014102328/http://www.networksandpathways.org/pathway?name=RANKL&description=RANKL RANKL Signaling Pathway]
* {{MeshName|RANKL+Protein}}
* {{PDBe-KB2|O14788|Tumor necrosis factor ligand superfamily member 11}}

{{PDB Gallery|geneid=8600}}
{{Clusters of differentiation}}
{{Tumor necrosis factors}}
{{Cytokine receptor modulators}}
{{NLM content}}
{{Use dmy dates|date=April 2017}}

[[Category:Cytokines]]
[[Category:Clusters of differentiation]]