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.

骨赘是在骨性关节炎(OA)、银屑病关节炎(PSA)和强直性脊柱炎(AS)退行性关节上形成的骨质突起，但在类风湿性关节炎(RA)中不是。骨赘的发育过程与软骨内成骨有关，软骨内成骨受生长因子如Wnt因子的调节。在缺乏骨赘的RA中，典型的Wnt拮抗剂Dkk1过度表达。阻断Dkk1诱导小鼠关节炎骨赘形成，暗示规范的Wnt信号促进骨赘形成。相反，我们已经证明，Wnt拮抗剂WiF-1缺乏干扰规范和非规范Wnt信号通路的小鼠，在血清诱导的关节炎(SIA)和实验性骨关节炎中表现出骨赘形成减少。因此，WiF-1促进骨赘的形成，表明受WiF-1调控的非规范Wnt信号可能抑制骨赘的形成。此外，在这些关节炎模型中，我们观察到WiF-1缺陷小鼠软骨损伤的加重，表明WiF-1对关节炎引发的软骨退化具有保护作用。我们的研究也可能解释一些关节炎如何形成骨赘，而另一些则不是：DKK1在RA中的过度表达是由肿瘤坏死因子α触发的。相反，我们发现肿瘤坏死因子α抑制WIF-1的表达，而WIF-1被骨赘相关细胞因子IL-17和-23上调。因此，促炎细胞因子可能通过分泌Wnt拮抗剂来调节规范和非规范Wnt信号的平衡，从而控制骨赘的形成。因此，本研究方案旨在解决以下问题：(I)在关节炎期间，WiF-1如何影响软骨和骨骼的改变？WIF-1是否通过调节非典型的Wnt信号通路来控制骨赘形成和软骨降解？WiF-1是否具有治疗关节疾病软骨退行性变的潜力？疾病特异性细胞因子信号是否控制规范和非规范Wnt信号的平衡，从而定义关节疾病的结构表型？为了证实这些假说，我们将在SIA和实验性骨关节炎期间研究WiF-1对骨赘形成和软骨退变机制的影响。特别是在这些过程中的规范和非规范的WNT信令将被研究。我们将进一步支持这样的假设，即阻断非规范的Wnt信号促进了SIA小鼠的骨赘形成。异位注射WiF-1治疗软骨退行性变的可能性将在SIA和实验性小鼠骨性关节炎中进行评估。最后，炎性和退行性关节疾病中的细胞因子谱将与Wnt拮抗剂基因在小鼠和人类患者中的表达和骨赘形成相关，并将在体外研究细胞因子对Wnt拮抗剂基因表达的调节。