骨硬化蛋白

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。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，并对骨形成具有抗合成代谢作用。 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）。 骨硬化蛋白是SOST基因的产物，位于人类染色体17q12–q21 上，最初被认为是一种非经典骨形态发生蛋白（BMP）拮抗剂。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。Wnt通路的抑制导致骨形成减少。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。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。 骨细胞产生的骨硬化蛋白受到甲状旁腺激素、机械负荷、雌激素和细胞因子（包括前列腺素E2、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。降钙素可增加骨硬化蛋白的产生。因此，成骨细胞活性由负反馈系统自我调节。 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。 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。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。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。这是一种非常罕见的病症，2002年大约有30例已知病例。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。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。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。 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。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。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。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。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%。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。骨硬化蛋白在牙科领域具有重要意义，并且正在开发针对骨硬化蛋白的再生策略。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。它还于2019年获准在日本和欧盟使用。 與骨硬化蛋白相關的疾病；在維基數據上查看/編輯參考.  GRCh38: Ensembl release 89: ENSG00000167941 - Ensembl, May 2017 GRCm38: Ensembl release 89: ENSMUSG00000001494 - Ensembl, May 2017 Human PubMed Reference:. 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