RESEARCH: What Wnt Wrong?

[Guest guest]

Source:

American Journal of Pathology

Date:

2005-06-23

Arthritis: What Wnt Wrong?

The cellular signaling protein Wnt, which is involved in embryonic

development and cancer, contributes to disease progression of both

rheumatoid arthritis and osteoarthritis. The article by Nakamura et

al., " Expression profiles and functional analyses of Wnt-related genes

in human joint disorders, " appears in the July issue of The American

Journal of Pathology and is accompanied by a commentary.

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 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