Arthritis: What Wnt Wrong?

Wnt is best known as a proto-oncogene because its disruption can lead to cancer in various organs such as colon, lung, and breast. However, mounting evidence also points to its involvement in arthritic joint disease. Comprehensive analysis of the entire Wnt gene family in the progression of arthritis has been lacking until now.

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 involved in arthritic joint disease. This extensive study, performed under the direction of Dr. Shigeyuki Wakitani, who is an assistant professor at the Department of Orthopedic Surgery, Shinshu University School of Medicine, examined joint tissue from patients who underwent total knee replacement for rheumatoid arthritis (RA), osteoarthritis (OA), or non-arthritic injury.

Using several molecular methods, Wakitani's group identified Wnt-7b and -10a as genes that were significantly upregulated in the arthritic knee tissues. However, protein expression studies revealed that only Wnt-7b was produced in arthritic joints, with strong protein localization to the synovium (or joint lining) and weak localization to cartilage and bone. In addition, strong Wnt-7b expression most frequently correlated with areas of high inflammation.

The authors also examined whether inflammatory cytokines were produced in primary cartilage and synovial cells from arthritic versus normal joints. While OA cells did not differ from controls, primary RA cells produced TNF-a, IL-1ß and IL-6 at levels 2- to 4-fold above controls. Importantly, this effect could be replicated in normal cells when they were engineered to express Wnt-7b, demonstrating the importance of Wnt-7b in the inflammatory response of RA.

The above findings identify a role for Wnt-7b in arthritic processes. Arthritic diseases manifest differently depending on the type, with RA exhibiting inflammation of the synovium and loss of cartilage and bone and OA exhibiting narrowing of joint space, loss of protective cartilage, and growth of bone cysts (or osteophytes).

Interestingly, Wnt-7b was strongly upregulated within joints at sites of disease manifestation: mainly in synovium of RA but in synovium, cartilage, osteophyte, and bone of OA. In addition, the findings that Wnt-7b was frequently found at sites of inflammation and elicited an inflammatory response are consistent with inflammation as a hallmark of RA disease.

Co-author Dr. Yukio Nakamura is an Orthopedic Surgeon at Shinshu University School of Medicine and is currently at Howard Hughes Medical Institute/Case Western Reserve University as a research associate. Nakamura has been studying the biological activities and signaling pathway of a Wnt-related gene that causes severe joint degenerative disease in humans.

"More specific analyses such as gain-of-function and loss-of-function study of Wnt-7b will give us a clue which Wnt-7b would be an important pathobiological factor in rheumatoid arthritis," added Nakamura. Future studies will investigate the role of Wnt and its signaling partners in arthritic joint destruction. Further delineation of the Wnt signaling pathway in arthritic progression may provide future therapies for the growing number of arthritis suffers.

According to The National Center for Health Statistics, over 42 million US adults, or 20% of the population, complained of arthritic symptoms in 2002.

All work was performed at Shinshu University School of Medicine in Nagano, Japan.

Nakamura Y, Nawata M, Wakitani S: Expression profiles and functional analyses of Wnt-related genes in human joint disorders. Am J Pathol 2005, 167: 97-105

Commentary: Ishikawa Y: Wnt signaling and orthopedic diseases. Am J Pathol 2005, 167: 1-3

The American Journal of Pathology, the official journal of the American Society for Investigative Pathology (ASIP), seeks to publish high-quality original papers on the cellular and molecular mechanisms of disease. The editors accept manuscripts which report important findings on disease pathogenesis or basic biological mechanisms that relate to disease, without preference for a specific method of analysis. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, biological, animal, chemical and immunological approaches in conjunction with morphology.