http://casemed.case.edu
Arthritis:
What Wnt wrong?
CLEVELAND (June 22, 2005) – 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
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-α, IL-1β 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 working as a research associate in the Howard Hughes
Medical Institute at the Case Western Reserve University School of Medicine.
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, more than 42 million
###
All work was performed at Shinshu University School of Medicine in
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.
###
For more Case Western Reserve University
School of Medicine news, see http://casemed.case.edu/public_affairs/news/archives.cfm.