Wnt inhibitory factor 1 (Wif-1) might uncouple bone and cartilage destruction in inflammatory arthritis. In a mouse model of rheumatoid arthritis (RA), mice deficient in Wif1 had more cartilage damage and less bone damage than mice with normal Wif-1 expression.

Credit: © 2013 American College of Rheumatology; reproduced with permission from John Wiley and Sons.

RA is associated with the destruction of both bone and cartilage. Transgenic mice overexpressing TNF (TNFtg) develop arthritis similar to RA, with synovial inflammation and destruction of both cartilage and bone. Michael Stock and colleagues examined chondrocytes and osteoblasts ex vivo, and found that TNF represses the expression of Wif-1, thereby stimulating canonical Wnt signalling. Wif-1 levels were also lower in TNFtg mice than in control mice, suggesting a role for Wif-1 in TNF-induced arthritis.

Using the TNFtg mouse, they then assessed the role of Wif-1 in arthritis. TNFtg mice and Wif1−/−;TNFtg mice both developed arthritis with similar levels of inflammation. Wif1−/−;TNFtg mice, however, had less arthritis-mediated loss of the trabecular bone than TNFtg mice did. More osteoclasts were found in TNFtg than in control mice; this increase was not observed in Wif1−/−;TNFtg mice. Osteoblast numbers were unaffected by Wif1 deficiency. Wif-1 might, therefore, increase osteoclast activity, thereby increasing bone loss in RA.

By contrast, more cartilage destruction and more proteoglycan loss were observed in Wif1−/−;TNFtg mice than in TNFtg mice. Transient overexpression of Wif-1 in TNFtg mice had the opposite effect; Wif-1 decreased the arthritis-related loss of proteoglycan and articular cartilage. In this model, Wif-1 protects cartilage but does not protect bone.

Other Wnt-modulating proteins have not shown this uncoupling effect. “Wif-1 is a very interesting molecule since it controls bone and cartilage damage in opposite directions,” explains Stock. “For future therapies targeting cartilage and bone damage, it will be important to understand how these two tissues interact in different types of arthritis.”