骨硬化蛋白

位於17號人類染色體的基因

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]

骨硬化蛋白
已知的结构
PDB直系同源搜索: PDBe RCSB
识别号
别名SOST;, CDD, SOST1, VBCH, DAND6, sclerostin, Sclerostin
外部IDOMIM605740 MGI1921749 HomoloGene11542 GeneCardsSOST
相关疾病
sclerosteosis 1[1]
基因位置(人类
17号染色体
染色体17号染色体[2]
17号染色体
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
物种人类小鼠
Entrez
Ensembl
UniProt
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]
维基数据
查看/编辑人类查看/编辑小鼠
骨硬化蛋白
鉴定
标志Sclerostin
PfamPF05463旧版
InterPro英语InterProIPR008835

结构

骨硬化蛋白长度为213个残基,其二级结构蛋白质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

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]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

编码骨硬化蛋白的基因突变与高骨量、骨质硬化症英语Sclerosteosis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长骨骨干中最为突出,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

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]欧盟使用。[40]

参考资料

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