RANKL

核因子κ-B配体受体致活剂; （RANKL）
	PDB rendering based on 1s55.
有效结构
PDB	直系同源检索：PDBe, RCSB
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	3URF
标识
代号	TNFSF11; CD254; ODF; OPGL; OPTB2; RANKL; TRANCE; hRANKL2; sOdf
扩展标识	遗传学：602642 鼠基因：1100089 同源基因：2744 GeneCards: TNFSF11 Gene
基因本体论描述
分子功能	· cytokine activity; · tumor necrosis factor receptor binding; · tumor necrosis factor receptor superfamily binding;
细胞成分	· extracellular region; · extracellular space; · cytoplasm; · integral to plasma membrane;
生物过程	· ossification; · monocyte chemotaxis; · immune response; · activation of JUN kinase activity; · organ morphogenesis; · positive regulation of intracellular protein kinase cascade; · cytokine-mediated signaling pathway; · osteoclast differentiation; · tumor necrosis factor-mediated signaling pathway; · mammary gland epithelial cell proliferation; · positive regulation of homotypic cell-cell adhesion; · positive regulation of I-kappaB kinase/NF-kappaB cascade; · positive regulation of MAP kinase activity; · bone resorption; · positive regulation of osteoclast differentiation; · positive regulation of bone resorption; · positive regulation of transcription from RNA polymerase II promoter; · positive regulation of JNK cascade; · positive regulation of T cell activation; · positive regulation of sequence-specific DNA binding transcription factor activity; · positive regulation of NF-kappaB transcription factor activity; · protein homooligomerization; · positive regulation of corticotropin-releasing hormone secretion; · positive regulation of protein kinase B signaling cascade; · mammary gland alveolus development; · ERK1 and ERK2 cascade; · positive regulation of fever generation by positive regulation of prostaglandin secretion; · TNFSF11-mediated signaling pathway; · positive regulation of ERK1 and ERK2 cascade via TNFSF11-mediated signaling;
	Sources: Amigo / QuickGO
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核因子κ-B配体受体致活剂（Receptor activator of nuclear factor kappa-B ligand，RANKL）又称NF-κB受体激活蛋白配体^[1]，是一种在人体中由“TNFSF基因”转译出来的蛋白质^[2]^[3]。

RANKL为肿瘤坏死因子（英语：tumor necrosis factor）超家族的一员，属于第二型穿膜蛋白^[4]。可以影响免疫系统和调控骨质新生和重塑。

RANKL在骨骼的新陈代谢方面，扮演著相当重要的角色。他是造骨细胞（osteoblast）膜上的一种膜蛋白（又被称为CD254），可以活化蚀骨细胞（osteoclast），会加速蚀骨细胞破坏骨质并被吸收，为骨质更新的重要一环。当造骨细胞膜上的RANKL，活化了蚀骨细胞膜上的RANK（英语：receptor activator of nuclear factor kappa-B (RANK)）蛋白，蚀骨作用就会开始。

RANKL的其他别名还有：“肿瘤坏死因子配体超家族成员11”（tumor necrosis factor ligand superfamily member 11，TNFSF11）、“肿瘤坏死因子相关诱导细胞因子”（TNF-related activation-induced cytokine，TRANCE）、“蚀骨细胞抑制因子配体”（osteoprotegerin ligand，OPGL）或蚀骨细胞分化因子（osteoclast differentiation factor，ODF）。

功能

RANKL是肿瘤坏死因子（英语：tumor necrosis factor）（tumor necrosis factor，TNF）超家族的一员，为蚀骨细胞抑制因子（英语：osteoprotegerin）（osteoprotegerin）的配体，属于一种Ⅱ型跨膜蛋白。RANKL可以增强成熟蚀骨细胞的活力，阻止破骨细胞凋亡。^[5]

免疫上，RANKL被视为是树突细胞的存活因子。在“依赖T免疫反应”的途径下（即反应必须经由辅助T细胞所致活），RANKL可阻止树突细胞凋亡，促进T淋巴细胞增殖，且在淋巴细胞的早期发育和淋巴结的器官发育中发挥决定性的作用，这些作用可被OPG阻断，而激活的T淋巴细胞表达的RANKL可直接促进蚀骨细胞生成，这些都提示OPG/RANK/RANKL系统可能是联系骨代谢与免疫系统之间的桥梁^[6]。

曾经有文献指出，T细胞的活化会刺激破骨细胞生成以及骨质流失。

此外，RANKL还可以透过与“SRC激酶（英语：Src (gene)）”（SRC kinase），以及“肿瘤坏死因子受体相关因子6”（tumor necrosis factor receptor-associated factor 6，TRAF6（英语：TRAF6））形成信息复合物，以致活AKT/PKB等细胞凋亡抑制激酶。这些迹象指出RANKL可能具有调节细胞凋亡的功能。^[7]

动物实验

实验发现，将TNFSF基因剔除掉的老鼠，会导致严重的骨质石化症（英语：Osteopetrosis）（Osteopetrosis），且会缺乏蚀骨细胞。此外，此种基因剔除鼠会在T淋巴球和B淋巴球的早期分化中，出现重大缺陷。且母鼠在怀孕期间的lobulo-alveolar mammary structures无法发育。^[7]

临床上的重要性

骨骼

如果人体制造了过多的RANKL，会造成各式各样的退化性骨骼疾病，例如类风湿性关节炎（rheumatoid arthritis）和干癣性关节炎（psoriatic arthritis）。第一项被FDA认可的RANKL抑制剂是denosumab抗体；其也可用来治疗女性更年期后的骨质疏松。

乳癌

服用含有醋酸甲羟孕酮（medroxyprogesterone acetate，MPA）的药物（一种合成黄体素，可应用于避孕以及替代激素疗法）会增加得到乳癌的风险。MPA会促使乳腺上皮中的RANKL大量分泌，而诱发乳癌。因此RANKL抑制剂可望被用作预防乳癌的药物。^[8]^[9]

参见

白血球分化抗原（Cluster of differentiation）
RANK（英语：RANK）
蚀骨细胞抑制因子（英语：Osteoprotegerin）
骨免疫学（英语：Osteoimmunology）

参考文献

^ https://www.termonline.cn/search?searchText=RANKL
^ Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS, Frankel WN, Lee SY, Choi Y. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J. Biol. Chem. October 1997, 272 (40): 25190–4. PMID 9312132. doi:10.1074/jbc.272.40.25190.
^ Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. November 1997, 390 (6656): 175–9. PMID 9367155. doi:10.1038/36593.
^ Hanada R, Hanada T, Sigl V, Schramek D, Penninger JM. RANKL/RANK-beyond bones. J. Mol. Med. 2011, 89 (7): 647–56. PMID 21445556. doi:10.1007/s00109-011-0749-z.
^ OPG-RANK-RANKL系统在溶骨性骨肿瘤中的应用（页面存档备份，存于互联网档案馆），张强
^ Theill LE，Boyle WJ，Penninger JM.RANKL and RANK：T cells，bone loss，and mammalian evolution(J).Annu Rev Immunol，2002
^ ^7.0 ^7.1 Entrez Gene: TNFSF11 tumor necrosis factor (ligand) superfamily, member 11.
^ 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. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature. November 2010, 468 (7320): 98–102. PMID 20881962. doi:10.1038/nature09387.
^ Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, Pinkas J, Branstetter D, Dougall WC. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature. November 2010, 468 (7320): 103–7. PMID 20881963. doi:10.1038/nature09495.

延伸阅读

Whyte M. The long and the short of bone therapy. N Engl J Med. 2006, 354 (8): 860–3. PMID 16495400. doi:10.1056/NEJMe068003. link（页面存档备份，存于互联网档案馆）
Buckley KA, Fraser WD. Receptor activator for nuclear factor kappaB ligand and osteoprotegerin: regulators of bone physiology and immune responses/potential therapeutic agents and biochemical markers.. Ann. Clin. Biochem. 2003, 39 (Pt 6): 551–6. PMID 12564836. doi:10.1258/000456302760413324.
Jeffcoate W. Vascular calcification and osteolysis in diabetic neuropathy-is RANK-L the missing link?. Diabetologia. 2005, 47 (9): 1488–92. PMID 15322748. doi:10.1007/s00125-004-1477-5.
Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin.. Circ. Res. 2005, 95 (11): 1046–57. PMID 15564564. doi:10.1161/01.RES.0000149165.99974.12.
Whyte MP, Mumm S. Heritable disorders of the RANKL/OPG/RANK signaling pathway.. Journal of musculoskeletal & neuronal interactions. 2005, 4 (3): 254–67. PMID 15615493.
Clohisy DR, Mantyh PW. Bone cancer pain and the role of RANKL/OPG.. Journal of musculoskeletal & neuronal interactions. 2005, 4 (3): 293–300. PMID 15615497.
Anandarajah AP, Schwarz EM. Anti-RANKL therapy for inflammatory bone disorders: Mechanisms and potential clinical applications.. J. Cell. Biochem. 2006, 97 (2): 226–32. PMID 16240334. doi:10.1002/jcb.20674.
Baud'huin M, Duplomb L, Ruiz Velasco C, Fortun Y, Heymann D, Padrines M. Key roles of the OPG-RANK-RANKL system in bone oncology.. Expert Rev Anticancer Ther. 2007, 7 (2): 221–32. PMID 17288531. doi:10.1586/14737140.7.2.221.
Yogo K, Ishida-Kitagawa N, Takeya T. Negative autoregulation of RANKL and c-Src signaling in osteoclasts.. J. Bone Miner. Metab. 2007, 25 (4): 205–10. PMID 17593489. doi:10.1007/s00774-007-0751-2.
Boyce BF, Xing L. Biology of RANK, RANKL, and osteoprotegerin.. Arthritis Res. Ther. 2007,. 9 Suppl 1: S1. PMC 1924516 . PMID 17634140. doi:10.1186/ar2165.
McClung M. Role of RANKL inhibition in osteoporosis.. Arthritis Res. Ther. 2007,. 9 Suppl 1: S3. PMC 1924518 . PMID 17634142. doi:10.1186/ar2167.

外部链接

RANKL引用了美国国家医学图书馆提供的资料，这些资料属于公共领域。

[1] ttps://www.termonline.cn/search?searchText=RANKL

[pmid9312132-2] Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS, Frankel WN, Lee SY, Choi Y. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J. Biol. Chem. October 1997, 272 (40): 25190–4. PMID 9312132. doi:10.1074/jbc.272.40.25190.

[pmid9367155-3] Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. November 1997, 390 (6656): 175–9. PMID 9367155. doi:10.1038/36593.

[pmid21445556-4] Hanada R, Hanada T, Sigl V, Schramek D, Penninger JM. RANKL/RANK-beyond bones. J. Mol. Med. 2011, 89 (7): 647–56. PMID 21445556. doi:10.1007/s00109-011-0749-z.

[Chang-5] OPG-RANK-RANKL系统在溶骨性骨肿瘤中的应用（页面存档备份，存于互联网档案馆），张强

[6] Theill LE，Boyle WJ，Penninger JM.RANKL and RANK：T cells，bone loss，and mammalian evolution(J).Annu Rev Immunol，2002

[entrez-7] 7.0 ^7.1 Entrez Gene: TNFSF11 tumor necrosis factor (ligand) superfamily, member 11.

[pmid20881962-8] 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. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature. November 2010, 468 (7320): 98–102. PMID 20881962. doi:10.1038/nature09387.

[pmid20881963-9] Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, Pinkas J, Branstetter D, Dougall WC. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature. November 2010, 468 (7320): 103–7. PMID 20881963. doi:10.1038/nature09495.

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