Wnts, Joints, and Knees

A new study appearing in the July 2005 issue of American Journal of Pathology targets the cellular signaling protein called Wnt as a contributor to the progression of both rheumatoid arthritis (RA) and osteoarthritis (OA). Entitled "Expression profiles and functional analyses of Wnt-related genes in human joint disorders," the study was conducted by Nakamura, Wakitani, et al.

Wnt activity is associated with a number of biological processes, including embryonic development and cancer metastasis. The protein itself is best known as a proto-oncogene because its disruption can lead to various types of cancer, including colon, lung, and breast cancer. However, accumulating evidence from previous research points to its additional involvement in arthritic joint disease.

For the study, the researchers at Shinshu University School of Medicine in Nagano, Japan, examined 19 members of the Wnt gene family to determine exactly which of these genes were linked to arthritic joint disease. In particular, the researchers examined joint tissue from patients who underwent total knee replacement due to either RA or OA.

Using several molecular methods, the group identified Wnt-7b and -10a as genes that were significantly upregulated in arthritic knee tissue samples (i.e. there was an increase in Wnt-7b and -10a receptors). However, protein expression studies revealed that only Wnt-7b was produced in arthritic joints, and was strongly localized in the joint lining (synovium) and little localization in cartilage and bone. In addition, strong Wnt-7b expression closely correlated with areas of high inflammation. This means that a large amount of Wnt-7b protein was found around areas of inflammation.

The authors also examined whether inflammatory cytokines (i.e. regulatory proteins involved in immune responses) were produced in cells taken from arthritic joints. While OA cells did not differ from controls, primary RA cells produced TNF-a, IL-1B and IL-6 at levels 2- to 4-fold above the controls. This effect was then replicated in normal cells when the cells were engineered to express Wnt-7b, thus demonstrating the importance of Wnt-7b in the inflammatory response of RA. Wnt-7b was strongly upregulated within joints at sites of disease manifestation, specifically in synovium of RA but in synovium, cartilage, osteophyte, and bone of OA. Also, the findings that Wnt-7b was frequently found at sites of inflammation and elicited an inflammatory response are consistent with the inflammation that usually accompanies RA disease.

The group suggests that much work is left to be done. More specific analyses, like a gain-of-function and loss-of-function study of Wnt-7b, will give researchers more insight into which Wnt-7b would be an important pathobiological factor in rheumatoid arthritis. Future studies will also investigate the role of Wnt and its signaling partners in arthritic joint destruction. Future therapies based on this research are in sight for the growing number of arthritis suffers.

Article References
http://www.mydna.com/genes/genetics/news/resources/news/200506/news_20050622_wnt.html, site accessed on 06/29/05