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骨硬化蛋白

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维基百科，自由的百科全书
骨硬化蛋白
已知的結構
PDB直系同源搜索: PDBe RCSB
識別號
别名SOST；, CDD, SOST1, VBCH, DAND6, sclerostin, Sclerostin
外部IDOMIM：605740 MGI：1921749 HomoloGene：11542 GeneCards：SOST
相關疾病
sclerosteosis 1[1]
基因位置（人类）
17號染色體
染色体17號染色體[2]
17號染色體
骨硬化蛋白的基因位置
骨硬化蛋白的基因位置
基因座17q21.31起始43,753,738 bp[2]
终止43,758,791 bp[2]
直系同源
物種人類小鼠
Entrez

50964

74499

Ensembl

ENSG00000167941

ENSMUSG00000001494

UniProt

Q9BQB4

Q99P68

mRNA​序列

NM_025237

NM_024449

蛋白序列

NP_079513

NP_077769

基因位置​（UCSC）Chr 17: 43.75 – 43.76 MbChr 11: 101.85 – 101.86 Mb
PubMed​查找[4][5]
維基數據
檢視/編輯人類檢視/編輯小鼠
骨硬化蛋白
鑑定
標誌Sclerostin
PfamPF05463（旧版）
InterPro（英语：InterPro）IPR008835

骨硬化蛋白（英语：Sclerostin）或译作硬骨素、硬骨抑素、抑硬素，是人类中由SOST基因编码的一种蛋白质。[6]它是一种分泌性糖蛋白，具有C端半胱氨酸结（英语：Cystine knot）样（CTCK）结构域，且与骨形态发生蛋白（BMP）拮抗剂DAN（英语：Poly(A)-specific ribonuclease）（神经母细胞瘤中差异筛选选择的基因异常）家族序列相似。骨硬化蛋白主要由骨细胞产生，但也在其他组织中表达，[7]并对骨形成具有抗合成代谢作用。[8]

结构

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骨硬化蛋白长度为213个残基，其二级结构经蛋白质NMR（英语：Nuclear magnetic resonance spectroscopy of proteins）测定为28% β折叠（6条链；32个残基）。[9]

功能

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骨硬化蛋白是SOST基因的产物，位于人类染色体17q12–q21 上，[10]最初被认为是一种非经典骨形态发生蛋白（BMP）拮抗剂。[11]最近，硬化蛋白已被鉴定为与LRP5（英语：LRP5）/6（英语：LRP6）受体结合并抑制Wnt信号通路。[12][13]Wnt通路的抑制导致骨形成减少。[12]尽管其潜在机制尚不清楚，但据信骨硬化蛋白对BMP诱导的骨形成的拮抗作用是由Wnt信号传导介导的，而不是BMP信号通路介导的。[14][15]硬化素在骨细胞和一些软骨细胞中表达，它抑制成骨细胞的骨形成。[16][17][18]

骨细胞产生的骨硬化蛋白受到甲状旁腺激素、[18][19]机械负荷、[20]雌激素[21]和细胞因子（包括前列腺素E2、[22]抑癌蛋白M、心肌营养素1（英语：Cardiotrophin 1）和白血病抑制因子）的抑制。[23]降钙素可增加骨硬化蛋白的产生。[24]因此，成骨细胞活性由负反馈系统自我调节。[25]

临床意义

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编码骨硬化蛋白的基因突变与高骨量、骨质硬化症（英语：Sclerosteosis）和范布赫姆病（英语：Van Buchem disease）相关的疾病有关。[10]

范布赫姆病是一种常染色体隐性遗传骨骼疾病，其特征是骨骼过度生长。[26]它于 1955 年首次被描述为“家族性全身性皮质骨质增生症”，并于1968年被赋予现在的名称。[26][27]过度的骨形成在头骨、下颌骨、锁骨、肋骨和长骨的骨干中最为突出，并且骨形成贯穿一生。[26]这是一种非常罕见的病症，2002年大约有30例已知病例。[26]1967年，范布赫姆（英语：Frans van Buchem）对15名荷兰裔患者的疾病进行了描述。[26]硬化症患者与范布赫姆病患者不同，因为他们通常较高且手部畸形。[28]1990年代末，Chiroscience（英语：Chiroscience）公司和开普敦大学的科学家确定该基因中的“单一突变”导致了这种疾病。[29]

骨硬化蛋白抗体

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主条目：罗莫索珠单抗（英语：Romosozumab）

由于骨硬化蛋白对骨骼的特异性，目前正在开发一种针对该蛋白的抗体。[16]在骨质疏松大鼠和猴子的临床前试验中，它的使用增加了骨骼生长。[30][31]在一项I期研究中，安进公司的单剂量抗硬化素抗体（罗莫索珠单抗（英语：Romosozumab））增加了健康男性和绝经后女性髋部和脊柱的骨密度，并且该药物具有良好的耐受性。[32]在一项II期试验中，骨质疏松女性接受一年的抗体治疗后，骨密度的增加程度高于双磷酸酯（英语：Bisphosphonate）和特立帕肽治疗；它有轻微的注射副作用。[17][33]礼来公司针对骨硬化蛋白的单克隆人类抗体的II期试验对绝经后妇女产生了积极影响。与安慰剂组相比，每月接受该抗体治疗一年后，脊柱和髋部的骨矿物质密度分别增加了18%和6%。[34]在一项III期试验中，与安慰剂组相比，绝经后妇女接受罗莫索珠单抗治疗一年可降低椎骨骨折的风险。与安慰剂组相比，它还增加了腰椎（13.3% vs 0.0%）、股骨颈（5.2% vs -0.7%）和全髋关节（6.8% vs 0.0%）的骨矿物质密度。各组之间的不良事件是平均的。[35]骨硬化蛋白在牙科领域具有重要意义，[36]并且正在开发针对骨硬化蛋白的再生策略。[37]2019年4月，美国食品和药物管理局批准罗莫索珠单抗用于骨质疏松性骨折（英语：Pathologic fracture）风险极高的女性。[38]它还于2019年获准在日本[39]和欧盟使用。[40]

参考资料

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  1. ^ 與骨硬化蛋白相關的疾病；在維基數據上查看/編輯參考. 
  2. ^ 2.0 2.1 2.2 GRCh38: Ensembl release 89: ENSG00000167941 - Ensembl, May 2017
  3. ^ 3.0 3.1 3.2 GRCm38: Ensembl release 89: ENSMUSG00000001494 - Ensembl, May 2017
  4. ^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  5. ^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  6. ^ Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. American Journal of Human Genetics. March 2001, 68 (3): 577–89. PMC 1274471 可免费查阅. PMID 11179006. doi:10.1086/318811. 
  7. ^ Hernandez P, Whitty C, John Wardale R, Henson FM. New insights into the location and form of sclerostin. Biochemical and Biophysical Research Communications. April 2014, 446 (4): 1108–13. PMID 24667598. doi:10.1016/j.bbrc.2014.03.079. 
  8. ^ Entrez Gene: SOST sclerosteosis. 
  9. ^ Weidauer SE, Schmieder P, Beerbaum M, Schmitz W, Oschkinat H, Mueller TD. NMR structure of the Wnt modulator protein Sclerostin. Biochemical and Biophysical Research Communications. February 2009, 380 (1): 160–5. PMID 19166819. doi:10.1016/j.bbrc.2009.01.062. 
  10. ^ 10.0 10.1 Van Bezooijen, R. L.; Papapoulos, S. E.; Hamdy, N. A.; Ten Dijke, P.; Löwik, C. W. Control of bone formation by osteocytes? Lessons from the rare skeletal disorders sclerosteosis and van Buchem disease. BoneKEy-Osteovision. 2005, 2 (12): 33–38. doi:10.1138/20050189. 
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  12. ^ 12.0 12.1 Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. The Journal of Biological Chemistry. May 2005, 280 (20): 19883–7. PMID 15778503. doi:10.1074/jbc.M413274200 可免费查阅. 
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  18. ^ 18.0 18.1 Bellido T, Saini V, Pajevic PD. Effects of PTH on osteocyte function. Bone. June 2013, 54 (2): 250–7. PMC 3552098 可免费查阅. PMID 23017659. doi:10.1016/j.bone.2012.09.016. 
  19. ^ Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O'Brien CA, et al. Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology. November 2005, 146 (11): 4577–83. PMID 16081646. doi:10.1210/en.2005-0239 可免费查阅. 
  20. ^ Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. The Journal of Biological Chemistry. February 2008, 283 (9): 5866–75. PMID 18089564. doi:10.1074/jbc.M705092200 可免费查阅. 
  21. ^ Appelman-Dijkstra, Natasha M.; Papapoulos, Socrates E. Modulating Bone Resorption and Bone Formation in Opposite Directions in the Treatment of Postmenopausal Osteoporosis. Drugs. 2015, 75 (10): 1049–1058. PMC 4498277 可免费查阅. PMID 26056029. doi:10.1007/s40265-015-0417-7. 
  22. ^ Genetos DC, Yellowley CE, Loots GG. Prostaglandin E2 signals through PTGER2 to regulate sclerostin expression. PLOS ONE. March 2011, 6 (3): e17772. Bibcode:2011PLoSO...617772G. PMC 3059227 可免费查阅. PMID 21436889. doi:10.1371/journal.pone.0017772 可免费查阅. 
  23. ^ Walker EC, McGregor NE, Poulton IJ, Solano M, Pompolo S, Fernandes TJ, et al. Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice. The Journal of Clinical Investigation. February 2010, 120 (2): 582–92. PMC 2810087 可免费查阅. PMID 20051625. doi:10.1172/JCI40568. 
  24. ^ Gooi JH, Pompolo S, Karsdal MA, Kulkarni NH, Kalajzic I, McAhren SH, et al. Calcitonin impairs the anabolic effect of PTH in young rats and stimulates expression of sclerostin by osteocytes (PDF). Bone. June 2010, 46 (6): 1486–97. PMID 20188226. doi:10.1016/j.bone.2010.02.018. hdl:11343/52365 可免费查阅. 
  25. ^ Postmenopauzale Osteoporose. 
  26. ^ 26.0 26.1 26.2 26.3 26.4 Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. Journal of Medical Genetics. February 2002, 39 (2): 91–7. PMC 1735035 可免费查阅. PMID 11836356. doi:10.1136/jmg.39.2.91. 
  27. ^ Fosmoe RJ, Holm RS, Hildreth RC. Van Buchem's disease (hyperostosis corticalis generalisata familiaris). A case report. Radiology. April 1968, 90 (4): 771–4. PMID 4867898. doi:10.1148/90.4.771. 
  28. ^ Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST) (PDF). Human Molecular Genetics. March 2001, 10 (5): 537–43. PMID 11181578. doi:10.1093/hmg/10.5.537 可免费查阅. 
  29. ^ Scientists find 'bone mass gene' in South Africans suffering from inherited disease. Oshkosh Northwestern (Oshkosh, Wisconsin). Associated Press. 26 May 1999: B5 [24 December 2018] –通过Newspapers.com. 
  30. ^ Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. Journal of Bone and Mineral Research. April 2009, 24 (4): 578–88. PMID 19049336. S2CID 1012895. doi:10.1359/jbmr.081206. 
  31. ^ Ominsky MS, Vlasseros F, Jolette J, Smith SY, Stouch B, Doellgast G, et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. Journal of Bone and Mineral Research. May 2010, 25 (5): 948–59. PMID 20200929. S2CID 206003762. doi:10.1002/jbmr.14 可免费查阅. 
  32. ^ Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. Journal of Bone and Mineral Research. January 2011, 26 (1): 19–26. PMID 20593411. S2CID 38080680. doi:10.1002/jbmr.173 可免费查阅. 
  33. ^ Reid, I. R. Osteoporosis treatment at ASBMR 2012. IBMS BoneKEy. 2012, 9. doi:10.1038/bonekey.2012.245. 
  34. ^ Recker RR, Benson CT, Matsumoto T, Bolognese MA, Robins DA, Alam J, et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density. Journal of Bone and Mineral Research. February 2015, 30 (2): 216–24. PMID 25196993. S2CID 25584452. doi:10.1002/jbmr.2351 可免费查阅. 
  35. ^ Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. The New England Journal of Medicine. October 2016, 375 (16): 1532–1543. PMID 27641143. doi:10.1056/NEJMoa1607948 可免费查阅. 
  36. ^ Samiei M, Janjić K, Cvikl B, Moritz A, Agis H. The role of sclerostin and dickkopf-1 in oral tissues - A review from the perspective of the dental disciplines. F1000Research. January 2019, 8: 128. PMC 6468704 可免费查阅. PMID 31031968. doi:10.12688/f1000research.17801.1 可免费查阅. 
  37. ^ Taut AD, Jin Q, Chung JH, Galindo-Moreno P, Yi ES, Sugai JV, et al. Sclerostin antibody stimulates bone regeneration after experimental periodontitis (PDF). Journal of Bone and Mineral Research. November 2013, 28 (11): 2347–56. PMID 23712325. S2CID 551897. doi:10.1002/jbmr.1984 可免费查阅. 
  38. ^ FDA approves romosozumab for osteoporosis. www.healio.com. April 9, 2019 [2019-05-11] （英语）. 
  39. ^ Kaplon H, Muralidharan M, Schneider Z, Reichert JM. Antibodies to watch in 2020. mAbs. 2020, 12 (1): 1703531. PMC 6973335 可免费查阅. PMID 31847708. doi:10.1080/19420862.2019.1703531. 
  40. ^ Victoria Rees. EC approves treatment for severe osteoporosis postmenopausal women. European Pharmaceutical Review. 13 December 2019 [27 February 2020]. 

延伸阅读

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外部链接

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