The role of Wif-1 and other secreted Wnt inhibitors in the control of Wnt signalling pathways during osteophyte formation

Wif-1和其他分泌性Wnt抑制剂在骨赘形成过程中控制Wnt信号通路的作用

• 批准号: 403036784
• 负责人: Privatdozent Dr. Michael Stock
• 金额: --
• 依托单位: Medizinische Klinik 3 - Rheumatologie und Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/403036784?language=en
• 关键词: role; Wif; other; secreted; Wnt

Osteophytes are bony protrusions forming on degenerating joints in osteoarthritis (OA), Psoriatic Arthritis (PsA), and Ankylosing Spondylitis (AS), but not in Rheumatoid Arthritis (RA). Osteophytes develop in a process related to endochondral ossification, which is regulated by growth factors such as Wnt factors. In RA, where osteophytes are absent, the canonical Wnt antagonist DKK1 is over-expressed. Blockade of DKK1 induces osteophyte formation in mouse arthritis, implying that canonical Wnt signalling promotes osteophyte formation. In contrast, we have shown that mice deficient in Wif-1, a Wnt antagonist interfering with both canonical and non-canonical Wnt-signalling pathways, exhibit reduced osteophyte formation in serum-induced arthritis (SIA) and in experimental OA. Thus, Wif-1 promotes osteophyte formation indicating that non-canonical Wnt signalling regulated by Wif-1may repress osteophyte formation. Moreover, we observed an aggravation of cartilage damage in Wif-1-deficient mice in these arthritis models, indicating that Wif-1 protects from arthritis-triggered cartilage degeneration. Our studies may also explain how some arthritides develop osteophytes, while others do not: Dkk1 overexpression in RA is triggered by TNFα. In contrast, we have shown that TNFα inhibits Wif-1 expression, while Wif-1 was upregulated by the osteophyte-associated cytokines IL-17 and -23. Hence, pro-inflammatory cytokines may control osteophyte formation by modulating the balance of canonical and non-canonical Wnt signalling via secreted Wnt antagonists. This research programme therefore aims to address the following questions:(i.) How does Wif-1 affect cartilage and bone alterations during arthritis?(ii.) Does Wif-1 control osteophyte formation and cartilage degradation via the regulation of non-canonical Wnt signalling pathways?(iii.) Does Wif-1 possess a therapeutic potential for the treatment of cartilage degeneration in joint diseases?(iv.) Does a disease-specific cytokine signature control the balance of canonical vs. non-canonical Wnt signalling, thereby defining the architectural phenotype of joint disease?To approve these hypotheses, the effect of Wif-1 on the mechanisms of osteophyte formation and cartilage degeneration will be investigated during SIA and experimental OA. Particularly canonical and non-canonical Wnt signalling during these processes will be studied. We will furthermore approve the hypothesis that the blockade of non-canonical Wnt signalling promotes osteophyte formation in mice with SIA. A possible therapeutical potential of ectopic Wif-1 administration in the treatment of cartilage degeneration will be evaluated in SIA and experimental OA in mice. Finally, cytokine profiles in inflammatory and degenerative joint diseases will be associated with Wnt antagonist gene expression and osteophyte formation in mice and in human patients and cytokine-dependent regulation of Wnt antagonist gene expression will be studied in vitro.

骨赘是骨关节炎（OA）、银屑病关节炎（PsA）和强直性脊柱炎（AS）中退行性关节上形成的骨突起，但在风湿性关节炎（RA）中不存在。骨赘在与软骨内骨化相关的过程中发育，该过程由生长因子如Wnt因子调节。在骨赘不存在的RA中，典型的Wnt拮抗剂DKK 1过表达。阻断DKK 1诱导小鼠关节炎中骨赘形成，这意味着经典Wnt信号传导促进骨赘形成。相比之下，我们已经表明，Wif-1（一种干扰经典和非经典Wnt信号传导途径的Wnt拮抗剂）缺陷的小鼠在血清诱导的关节炎（SIA）和实验性OA中表现出骨赘形成减少。因此，Wif-1促进骨赘形成，表明由Wif-1调节的非经典Wnt信号传导可能抑制骨赘形成。此外，我们在这些关节炎模型中观察到Wif-1缺陷小鼠的软骨损伤加重，表明Wif-1可以防止关节炎引发的软骨退化。我们的研究也可以解释一些关节炎如何形成骨赘，而另一些则没有：RA中Dkk 1的过度表达是由TNFα触发的。相反，我们发现TNFα抑制Wif-1的表达，而Wif-1被骨赘相关细胞因子IL-17和IL-23上调。因此，促炎细胞因子可以通过分泌的Wnt拮抗剂调节经典和非经典Wnt信号传导的平衡来控制骨赘形成。因此，本研究计划旨在解决以下问题：（一）Wif-1如何影响关节炎期间的软骨和骨改变？（二）Wif-1是否通过调节非经典Wnt信号通路来控制骨赘形成和软骨降解？（三）Wif-1是否具有治疗关节疾病中软骨退变的治疗潜力？（iv.）疾病特异性细胞因子特征是否控制经典与非经典Wnt信号传导的平衡，从而定义关节疾病的结构表型？为了证实这些假设，将在SIA和实验性OA期间研究Wif-1对骨赘形成和软骨退化机制的影响。特别是典型和非典型的Wnt信号在这些过程中将进行研究。我们将进一步证实非经典Wnt信号传导的阻断促进SIA小鼠骨赘形成的假设。将在小鼠的SIA和实验性OA中评价异位Wif-1施用在治疗软骨变性中的可能治疗潜力。最后，炎症性和退行性关节疾病中的细胞因子谱将与小鼠和人类患者中的Wnt拮抗剂基因表达和骨赘形成相关，并且将在体外研究Wnt拮抗剂基因表达的精氨酸依赖性调节。