維基百科

骨硬化蛋白

位於17號人類染色體的基因

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]它是一種分泌性醣蛋白，具有C端半胱氨酸結（英語：Cystine knot）樣（CTCK）結構域，且與骨形態發生蛋白（BMP）拮抗劑DAN（英語：Poly(A)-specific ribonuclease）（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]

骨硬化蛋白
已知的結構
PDB直系同源搜尋: PDBe RCSB
識別號
別名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（人類）
17號染色體
染色體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]
終止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（舊版）
InterPro（英語：InterPro）IPR008835

結構

骨硬化蛋白長度為213個殘基，其二級結構經蛋白質NMR（英語：Nuclear magnetic resonance spectroscopy of proteins）測定為28% β摺疊（6條鏈；32個殘基）。[9]

功能

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（英語：LRP5）/6（英語：LRP6）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副甲狀腺激素、[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（英語：Cardiotrophin 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

編碼骨硬化蛋白的基因突變與高骨量、骨質硬化症（英語：Sclerosteosis）和范布赫姆病（英語：Van Buchem disease）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（英語：Frans van Buchem）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（英語：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

主條目：羅莫索珠單抗（英語：Romosozumab）

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（英語：Romosozumab））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（英語：Bisphosphonate）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（英語：Pathologic fracture）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

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外部連結

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