摘要

Sclerostin, an inhibitor of the Wnt/β-catenin pathway, has anti-anabolic effects on bone formation by negatively regulating osteoblast differentiation. Mutations in the human sclerostin gene (SOST) lead to sclerosteosis with progressive skeletal overgrowth, whereas sclerostin-deficient (Sost(-/-)) mice exhibit increased bone mass and strength. Therefore, antibody-mediated inhibition of sclerostin is currently being clinically evaluated for the treatment of postmenopausal osteoporosis in humans. We report that in chronic TNFα (tumor necrosis factor α)-dependent arthritis, fibroblast-like synoviocytes constitute a major source of sclerostin and that either the lack of sclerostin or its antibody-mediated inhibition leads to an acceleration of rheumatoid arthritis (RA)-like disease in human TNFα transgenic (hTNFtg) mice with enhanced pannus formation and joint destruction. Inhibition of sclerostin also failed to improve clinical signs and joint destruction in the partially TNFα-dependent glucose-6-phosphate isomerase-induced arthritis mouse model, but ameliorated disease severity in K/BxN serum transfer-induced arthritis mouse model, which is independent of TNF receptor signaling, thus suggesting a specific role for sclerostin in TNFα signaling. Sclerostin effectively blocked TNFα- but not interleukin-1-induced activation of p38, a key step in arthritis development, pointing to a previously unrealized protective role of sclerostin in TNF-mediated chronic inflammation. The possibility of anti-sclerostin antibody treatment worsening clinical RA outcome under chronic TNFα-dependent inflammatory conditions in mice means that caution should be taken both when considering such treatment for inflammatory bone loss in RA and when using anti-sclerostin antibodies in patients with TNFα-dependent comorbidities. 

译文

Sclerosstin 是 Wnt/β-连环蛋白通路的抑制剂,通过负调节成骨细胞分化对骨形成具有抗合成代谢作用。人类 sclerostin 基因 (SOST) 的突变会导致骨质硬化和进行性骨骼过度生长,而 sclerostin 缺陷 (Sost (-/-)) 小鼠则会增加骨量和骨强度。因此,抗体介导的 sclerosstin 抑制目前正在临床评估用于治疗人类绝经后骨质疏松症。我们报道在慢性 tnf α (肿瘤坏死因子 α) 依赖性关节炎中, 成纤维样滑膜细胞构成硬化蛋白的主要来源,硬化蛋白的缺乏或其抗体介导的抑制导致类风湿关节炎 (RA) 的加速人 tnf α 转基因 (hTNFtg) 小鼠的-样疾病,血管内皮形成和关节破坏增强。在部分 tnf α 依赖性葡萄糖-6-磷酸异构酶诱导的关节炎小鼠模型中,sclerostin 的抑制也未能改善临床症状和关节破坏, 但是 K/BxN 血清转移诱导的关节炎小鼠模型的疾病严重程度有所改善,该模型独立于 TNF 受体信号传导,因此表明 sclerostin 在 TNF α 信号传导中的特定作用。Sclerostin 有效地阻止了 TNF α,但不 interleukin-1-induced p38 的激活,这是关节炎发展的关键一步,指出 sclerostin 在 TNF 介导的慢性炎症中以前未意识到的保护作用。在慢性 tnf α 依赖性炎症条件下,抗硬化蛋白抗体治疗恶化 RA 临床结果的可能性意味着在考虑 RA 炎症性骨丢失的治疗和在 tnf α 依赖性合并症患者中使用抗 sclerostin 抗体。

Sclerostin

内分泌 蛋白质 治疗药物
概述  :  

硬化蛋白是人类中由SOST 基因编码的一种蛋白质。硬化蛋白是一种分泌的糖蛋白,具有C端半胱氨酸结样(CTCK)结构域,其序列与骨形态发生蛋白(BMP)拮抗剂DAN(神经母细胞瘤中差异筛选选择的基因异常)家族相似。硬化蛋白主要由骨细胞产生,但也可在其他组织中表达,并且对骨形成具有抗合成代谢作用。机制硬化蛋白是SOST基因的产物,位于人的17q12–q21染色体上。最近,硬化蛋白已被鉴定为与LRP5/6受体结合并抑制Wnt信号通路,对Wnt途径的抑制导致减少的骨形成。尽管潜在的机制尚不清楚,但是

Sclerostin

释    义   硬化蛋白

例    句   Moreover, serum levels of sclerostin were significantly lower in patients with AS than in healthy individuals. 而且,AS病人血清硬化蛋白水平显著低于健康人群。

请扫描右侧二维码,免费查看词汇专业知识背景