The Role of the Wnt antagonist Wif-1 in bone remodelling during arthritis

慢性炎症性关节炎的特征是以软骨损伤和骨侵蚀为基础的持续性滑膜炎症和进行性关节破坏。WNT信号似乎将炎症与关节炎的结构损害联系起来。我们以前已经证明，Wnt拮抗剂DKK-1是关节炎关节重塑的关键介质，也是在这种疾病中观察到的骨侵蚀的主要部分。然而，Wnt信号的其他拮抗剂是否可能在关节炎中发挥类似的作用，还远未得到证实。我们提供的证据表明，Wnt拮抗剂Wnt抑制因子1(WiF-1)主要在关节软骨的浅层表达。此外，我们还发现WiF-1直接与在RA中高表达的Wnt蛋白结合。因此，WIF-1是观察到的关节炎关节重塑的有吸引力的候选者。拟议的项目将调查WiF-1在关节炎中的潜在参与。我们将分析Wnt信号分子在关节炎中的表达和调节，并在小鼠关节炎模型中使用获得和丧失功能的方法来研究WiF-1的潜在作用。最后，将检测WIF-1和其他Wnt信号分子在人类关节疾病中的表达。

Chronic inflammatory arthritis is characterized by perpetuating synovial inflammation and progressive joint destruction based on cartilage damage and bone erosion. Wnt signals appear to link inflammation to structural damage in arthritis. We have previously shown that the Wnt antagonist Dkk-1 is a key mediator of arthritic joint remodelling and accounts for the major part of bone erosion observed in this disease. However, if other antagonists of Wnt signalling may play a similar role in arthritis, is much less established. We have provided evidence that the Wnt antagonist Wnt inhibitory factor 1 (Wif-1) is predominantly expressed at superficial layers of articular cartilage. Moreover, we showed that Wif-1 directly binds to Wnt proteins, which are highly expressed in RA. Hence, Wif-1 is an attractive candidate for joint remodelling observed in arthritis. The proposed project will investigate a potential involvement of Wif-1 in arthritis. We will analyze expression and regulation of Wnt signalling molecules in arthritis and investigate a potential role for Wif-1 using gain- and loss-of-function approaches in murine arthritis models. Finally, expression of Wif-1 and other Wnt signalling molecules will be examined in human joint disease.