骨硬化蛋白
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骨硬化蛋白 | |||||||||
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鑑定 | |||||||||
標誌 | Sclerostin | ||||||||
Pfam | PF05463(舊版) | ||||||||
InterPro | IPR008835 | ||||||||
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骨硬化蛋白(英語:Sclerostin)或譯作硬骨素、硬骨抑素、抑硬素,是人類中由SOST基因編碼的一種蛋白質。[6]它是一種分泌性糖蛋白,具有C端半胱氨酸結樣(CTCK)結構域,且與骨形態發生蛋白(BMP)拮抗劑DAN(神經母細胞瘤中差異篩選選擇的基因異常)家族序列相似。骨硬化蛋白主要由骨細胞產生,但也在其他組織中表達,[7]並對骨形成具有抗合成代謝作用。[8]
結構
[編輯]骨硬化蛋白長度為213個殘基,其二級結構經蛋白質NMR測定為28% β摺疊(6條鏈;32個殘基)。[9]
功能
[編輯]骨硬化蛋白是SOST基因的產物,位於人類染色體17q12–q21 上,[10]最初被認為是一種非經典骨形態發生蛋白(BMP)拮抗劑。[11]最近,硬化蛋白已被鑑定為與LRP5/6受體結合併抑制Wnt信號通路。[12][13]Wnt通路的抑制導致骨形成減少。[12]儘管其潛在機制尚不清楚,但據信骨硬化蛋白對BMP誘導的骨形成的拮抗作用是由Wnt信號傳導介導的,而不是BMP信號通路介導的。[14][15]硬化素在骨細胞和一些軟骨細胞中表達,它抑制成骨細胞的骨形成。[16][17][18]
骨細胞產生的骨硬化蛋白受到甲狀旁腺激素、[18][19]機械負荷、[20]雌激素[21]和細胞因子(包括前列腺素E2、[22]抑癌蛋白M、心肌營養素1和白血病抑制因子)的抑制。[23]降鈣素可增加骨硬化蛋白的產生。[24]因此,成骨細胞活性由負反饋系統自我調節。[25]
臨床意義
[編輯]編碼骨硬化蛋白的基因突變與高骨量、骨質硬化症和范布赫姆病相關的疾病有關。[10]
范布赫姆病是一種常染色體隱性遺傳骨骼疾病,其特徵是骨骼過度生長。[26]它於 1955 年首次被描述為「家族性全身性皮質骨質增生症」,並於1968年被賦予現在的名稱。[26][27]過度的骨形成在頭骨、下頜骨、鎖骨、肋骨和長骨的骨幹中最為突出,並且骨形成貫穿一生。[26]這是一種非常罕見的病症,2002年大約有30例已知病例。[26]1967年,范布赫姆對15名荷蘭裔患者的疾病進行了描述。[26]硬化症患者與范布赫姆病患者不同,因為他們通常較高且手部畸形。[28]1990年代末,Chiroscience公司和開普敦大學的科學家確定該基因中的「單一突變」導致了這種疾病。[29]
骨硬化蛋白抗體
[編輯]由於骨硬化蛋白對骨骼的特異性,目前正在開發一種針對該蛋白的抗體。[16]在骨質疏鬆大鼠和猴子的臨床前試驗中,它的使用增加了骨骼生長。[30][31]在一項I期研究中,安進公司的單劑量抗硬化素抗體(羅莫索珠單抗)增加了健康男性和絕經後女性髖部和脊柱的骨密度,並且該藥物具有良好的耐受性。[32]在一項II期試驗中,骨質疏鬆女性接受一年的抗體治療後,骨密度的增加程度高於雙磷酸酯和特立帕肽治療;它有輕微的注射副作用。[17][33]禮來公司針對骨硬化蛋白的單克隆人類抗體的II期試驗對絕經後婦女產生了積極影響。與安慰劑組相比,每月接受該抗體治療一年後,脊柱和髖部的骨礦物質密度分別增加了18%和6%。[34]在一項III期試驗中,與安慰劑組相比,絕經後婦女接受羅莫索珠單抗治療一年可降低椎骨骨折的風險。與安慰劑組相比,它還增加了腰椎(13.3% vs 0.0%)、股骨頸(5.2% vs -0.7%)和全髖關節(6.8% vs 0.0%)的骨礦物質密度。各組之間的不良事件是平均的。[35]骨硬化蛋白在牙科領域具有重要意義,[36]並且正在開發針對骨硬化蛋白的再生策略。[37]2019年4月,美國食品和藥物管理局批准羅莫索珠單抗用於骨質疏鬆性骨折風險極高的女性。[38]它還於2019年獲准在日本[39]和歐盟使用。[40]
參考資料
[編輯]- ^ 與骨硬化蛋白相關的疾病;在維基數據上查看/編輯參考.
- ^ 2.0 2.1 2.2 GRCh38: Ensembl release 89: ENSG00000167941 - Ensembl, May 2017
- ^ 3.0 3.1 3.2 GRCm38: Ensembl release 89: ENSMUSG00000001494 - Ensembl, May 2017
- ^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ 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
. PMID 11179006. doi:10.1086/318811.
- ^ 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.
- ^ Entrez Gene: SOST sclerosteosis.
- ^ 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.
- ^ 10.0 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.
- ^ Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. The EMBO Journal. December 2003, 22 (23): 6267–76. PMC 291840
. PMID 14633986. doi:10.1093/emboj/cdg599.
- ^ 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
.
- ^ Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, Krumlauf R. Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. Journal of Bone and Mineral Research. November 2006, 21 (11): 1738–49. PMID 17002572. S2CID 28614850. doi:10.1359/jbmr.060810
.
- ^ van Bezooijen RL, Svensson JP, Eefting D, Visser A, van der Horst G, Karperien M, et al. Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. Journal of Bone and Mineral Research. January 2007, 22 (1): 19–28. PMID 17032150. S2CID 9235535. doi:10.1359/jbmr.061002
.
- ^ Krause C, Korchynskyi O, de Rooij K, Weidauer SE, de Gorter DJ, van Bezooijen RL, et al. Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways. The Journal of Biological Chemistry. December 2010, 285 (53): 41614–26. PMC 3009889
. PMID 20952383. doi:10.1074/jbc.M110.153890
.
- ^ 16.0 16.1 Bonewald LF. The amazing osteocyte. Journal of Bone and Mineral Research. February 2011, 26 (2): 229–38. PMC 3179345
. PMID 21254230. doi:10.1002/jbmr.320.
- ^ 17.0 17.1 Burgers TA, Williams BO. Regulation of Wnt/β-catenin signaling within and from osteocytes. Bone. June 2013, 54 (2): 244–9. PMC 3652284
. PMID 23470835. doi:10.1016/j.bone.2013.02.022.
- ^ 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
. PMID 23017659. doi:10.1016/j.bone.2012.09.016.
- ^ 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
.
- ^ 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
.
- ^ 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
. PMID 26056029. doi:10.1007/s40265-015-0417-7.
- ^ 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
. PMID 21436889. doi:10.1371/journal.pone.0017772
.
- ^ 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
. PMID 20051625. doi:10.1172/JCI40568.
- ^ 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
.
- ^ Postmenopauzale Osteoporose.
- ^ 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
. PMID 11836356. doi:10.1136/jmg.39.2.91.
- ^ 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.
- ^ 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
.
- ^ 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] –透過Newspapers.com.
- ^ 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.
- ^ 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
.
- ^ 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
.
- ^ Reid, I. R. Osteoporosis treatment at ASBMR 2012. IBMS BoneKEy. 2012, 9. doi:10.1038/bonekey.2012.245.
- ^ 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
.
- ^ 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
.
- ^ 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
. PMID 31031968. doi:10.12688/f1000research.17801.1
.
- ^ 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
.
- ^ FDA approves romosozumab for osteoporosis. www.healio.com. April 9, 2019 [2019-05-11] (英語).
- ^ Kaplon H, Muralidharan M, Schneider Z, Reichert JM. Antibodies to watch in 2020. mAbs. 2020, 12 (1): 1703531. PMC 6973335
. PMID 31847708. doi:10.1080/19420862.2019.1703531.
- ^ Victoria Rees. EC approves treatment for severe osteoporosis postmenopausal women. European Pharmaceutical Review. 13 December 2019 [27 February 2020].
延伸閱讀
[編輯]- Balemans W, Van Hul W. Human genetics of SOST. Journal of Musculoskeletal & Neuronal Interactions. 2007, 6 (4): 355–6. PMID 17185822.
- 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
. PMID 11836356. doi:10.1136/jmg.39.2.91.
- Staehling-Hampton K, Proll S, Paeper BW, Zhao L, Charmley P, Brown A, et al. A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. American Journal of Medical Genetics. June 2002, 110 (2): 144–52. PMID 12116252. doi:10.1002/ajmg.10401.
- Balemans W, Foernzler D, Parsons C, Ebeling M, Thompson A, Reid DM, et al. Lack of association between the SOST gene and bone mineral density in perimenopausal women: analysis of five polymorphisms. Bone. October 2002, 31 (4): 515–9. PMID 12398949. doi:10.1016/S8756-3282(02)00844-X.
- Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, et al. The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. Genome Research. October 2003, 13 (10): 2265–70. PMC 403697
. PMID 12975309. doi:10.1101/gr.1293003.
- Sevetson B, Taylor S, Pan Y. Cbfa1/RUNX2 directs specific expression of the sclerosteosis gene (SOST). The Journal of Biological Chemistry. April 2004, 279 (14): 13849–58. PMID 14739291. doi:10.1074/jbc.M306249200
.
- van Bezooijen RL, Roelen BA, Visser A, van der Wee-Pals L, de Wilt E, Karperien M, et al. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. The Journal of Experimental Medicine. March 2004, 199 (6): 805–14. PMC 2212719
. PMID 15024046. doi:10.1084/jem.20031454.
- Winkler DG, Yu C, Geoghegan JC, Ojala EW, Skonier JE, Shpektor D, et al. Noggin and sclerostin bone morphogenetic protein antagonists form a mutually inhibitory complex. The Journal of Biological Chemistry. August 2004, 279 (35): 36293–8. PMID 15199066. doi:10.1074/jbc.M400521200
.
- Zhang Z, Henzel WJ. Signal peptide prediction based on analysis of experimentally verified cleavage sites. Protein Science. October 2004, 13 (10): 2819–24. PMC 2286551
. PMID 15340161. doi:10.1110/ps.04682504.
- Sutherland MK, Geoghegan JC, Yu C, Turcott E, Skonier JE, Winkler DG, Latham JA. Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation. Bone. October 2004, 35 (4): 828–35. PMID 15454089. doi:10.1016/j.bone.2004.05.023.
- Uitterlinden AG, Arp PP, Paeper BW, Charmley P, Proll S, Rivadeneira F, et al. Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites. American Journal of Human Genetics. December 2004, 75 (6): 1032–45. PMC 1182139
. PMID 15514891. doi:10.1086/426458.
- Winkler DG, Sutherland MS, Ojala E, Turcott E, Geoghegan JC, Shpektor D, et al. Sclerostin inhibition of Wnt-3a-induced C3H10T1/2 cell differentiation is indirect and mediated by bone morphogenetic proteins. The Journal of Biological Chemistry. January 2005, 280 (4): 2498–502. PMID 15545262. doi:10.1074/jbc.M400524200
.
- Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Löwik CW, Reeve J. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB Journal. November 2005, 19 (13): 1842–4. PMID 16123173. S2CID 17000496. doi:10.1096/fj.05-4221fje.
- Gardner JC, van Bezooijen RL, Mervis B, Hamdy NA, Löwik CW, Hamersma H, et al. Bone mineral density in sclerosteosis; affected individuals and gene carriers. The Journal of Clinical Endocrinology and Metabolism. December 2005, 90 (12): 6392–5. PMID 16189254. doi:10.1210/jc.2005-1235
.