The protective function of the Wnt inhibitor sclerostin in inflammatory bone destruction.

Wnt 抑制剂硬化素在炎症性骨质破坏中的保护作用。

• 批准号: 159725117
• 负责人: Dr. Berno Dankbar, Ph.D.
• 金额: --
• 依托单位: Institut für Muskuloskelettale Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/159725117?language=en
• 关键词: protective; function; Wnt; inhibitor; sclerostin

In the past funding period, we could demonstrate that genetic deficiency or pharmacological inhibition of sclerostin led to a deterioration of disease severity in the TNFalpha-dependent arthritis mouse model (hTNFtg). hTNFtg mice that lack sclerostin or that were treated with sclerostin antibodies displayed enhanced joint inflammation, cartilage loss and bone erosion. Mechanistically, sclerostin effectively blocked TNF-induced signalling pathways, e.g. activation of p38, NFkappaB, key steps in arthritis development. Blockade appeared to involve LRP6 but was independent of the canonical Wnt-signalling pathway. Application of additional mouse models, such as the G6PI and the K/BxN serum transfer arthritis obviously revealed that the disease-promoting effect of sclerostin inhibition is dependent on the magnitide of how TNF participates in arthritis development. Our entire results obtained in the previous funding period, strongly indicates that sclerostin has a so far unknown protective role in chronic inflammation and inflammatory bone loss.These observations are of pivotal importance since inhibitors of sclerostin have been developed for the treatment of degenerative bone diseases and antibody-mediated inhibition of sclerostin is currently evaluated clinically for the treatment of postmenopausal osteoporosis in humans. Thus, it is of critical importance to investigate in more detail the role of sclerostin in inflammatory bone loss.The main objective of this project is the verification of a general protective effect of sclerostin on the TNF-dependent development of local bone erosions. For this purpose, we will compare various TNF-dependent mouse models (sclerostin knockout/antibody-treated and sclerostin-treated). For the assessment whether the lack of fibroblast-specific LRP6 is crucial for bone destruction, fibroblast-specific conditional knockouts will be compared with corresponding arthritic wt and Sost ko as well as with antibody-treated mice. The project will also include the identification and functional analyses of cytokine pathways inhibited by sclerostin in synovial fibroblasts and osteoblasts. Furthermore, the mechanism by which sclerostin/LRP6 interacts with TNFR or other cytokine receptors to inhibit signal transduction will be one of the main aspects of our project. Finally, we will investigate whether sclerostin modulates cytokine-mediated effects on proliferation, migration, apoptosis and invasive capacity of synovial fibroblasts as well as on osteoblast activity and apoptosis.

在过去的资助期间，我们可以证明，遗传缺陷或硬化素的药理学抑制导致TNFa依赖性关节炎小鼠模型（hTNFtg）中疾病严重程度的恶化。缺乏sclerostin或用sclerostin抗体治疗的hTNFtg小鼠显示出增强的关节炎症、软骨损失和骨侵蚀。从机制上讲，sclerostin有效地阻断了TNF诱导的信号传导途径，例如p38、NF κ B的激活，这是关节炎发展的关键步骤。阻断似乎涉及LRP 6，但独立于经典的Wnt信号通路。应用其他小鼠模型，如G6 PI和K/BxN血清转移性关节炎，明显揭示了硬化蛋白抑制的疾病促进作用依赖于TNF如何参与关节炎发展的程度。我们在上一个资助期获得的全部结果强烈表明，sclerostin在慢性炎症和炎性骨丢失中具有迄今未知的保护作用。这些观察结果具有关键重要性，因为sclerostin抑制剂已被开发用于治疗退行性骨疾病，并且抗体介导的sclerostin抑制目前正在临床上评估用于治疗人类绝经后骨质疏松症。因此，它是至关重要的，以调查更详细的sclerostin在炎症性骨loss.The主要目标的作用这个项目是一个一般的保护作用sclerostin对TNF依赖性发展的局部骨侵蚀的验证。为此，我们将比较各种TNF依赖性小鼠模型（sclerostin敲除/抗体处理和sclerostin处理）。为了评估成纤维细胞特异性LRP 6的缺乏是否对骨破坏至关重要，将成纤维细胞特异性条件性敲除与相应的关节炎wt和Sost ko以及与抗体处理的小鼠进行比较。该项目还将包括滑膜成纤维细胞和成骨细胞中sclerostin抑制的细胞因子途径的鉴定和功能分析。此外，sclerostin/LRP 6与TNFR或其他细胞因子受体相互作用抑制信号转导的机制将是我们项目的主要方面之一。最后，我们将研究sclerostin是否调节滑膜成纤维细胞的增殖，迁移，凋亡和侵袭能力，以及成骨细胞活性和凋亡的苦参碱介导的影响。

项目成果

P081 Sclerostin affects rankl-mediated osteoclast differentiation

P081â硬化素影响Rankl介导的破骨细胞分化

• DOI: 10.1136/annrheumdis-2018-ewrr2018.98
• 发表时间: 2018
• 期刊: Annals of the Rheumatic Diseases
• 影响因子: 27.4
• 作者: Intemann J;Wehmeyer C;Kracke V;Werbenko E;Paruzel P;Kramer I;Kneissel M;Dankbar B
• 通讯作者: Dankbar B