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

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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.