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Lack of Specific Collagen Type Leads to Osteoarthritis

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Duke Health News 919-660-1306

DURHAM, N.C. – Duke University Medical Center researchers have found that
joints whose cartilage lacks a specific type of collagen will develop
osteoarthritis – the so-called "wear-and-tear" form of the disease – at a
greatly accelerated rate.

The results of their experiments with mice provide new insights that
could lead to potential treatments for a disease that afflicts more than 40
million Americans, said the researchers.

The researchers found that mice lacking the gene that controls the
production of type VI collagen developed osteoarthritis at a rate more than
five times greater than mice with a functioning gene. Collagen is a
ubiquitous protein found throughout the body in connective tissue, muscle,
cartilage and bone. To date, 27 different types have been identified.

To examine structures within the cartilage of mouse joints, Leonidas
Alexopoulos, Ph.D., developed a novel "micro-vacuuming" technique. With this
device, Alexopoulos extracted key structures within the cartilage of mouse
hip joints, which are the size of the ball in a ball-point pen, and analyzed
how they responded to the stresses of everyday life.

Alexopoulos presented the results of the Duke study Feb. 20, 2005, at the
51th annual scientific meeting of the Orthopedic Research Society in
Washington, D.C. Alexopoulos, now a post-doctoral fellow at the
Massachusetts Institute of Technology, conducted the research in the
laboratory of Farshid Guilak, Ph.D., director of orthopedic research and
senior member of the Duke team. The study was funded by the National
Institutes of Health.

The researchers focused their attention on the narrow region of tissue
that surrounds the cartilage cells on the surface of joints and is known as
the pericellular matrix (PCM). Together with cartilage cells known as
chondrocytes, collagen types II, VI and IX, and other proteins, the PCM
forms a structure called a chondron, which is believed to provide a "buffer"
zone between the cells and the remainder of the cartilage tissue.

"The interesting thing is that type VI collagen occurs nowhere else in
the cartilage but the PCM, and no one really understood why," Alexopoulos
explained. "When we analyzed the PCM of mice unable to produce type VI
collagen, we found that the chondrons in these mice were much softer and the
joints did not respond well to mechanical pressures. The joint looked as if
it osteoarthritis had developed.

"It appears now that the type VI collagen acts like a scaffold that
provides structure and stiffness to the PCM," Alexopoulos continued. "With
this model for osteoarthritis, we have a better understanding of how changes
in the mechanical forces on the cells may lead to degeneration of the
cartilage."

For their experiments, the team compared how chondrons changed over time
in three different groups of mice: one group had functioning type VI
collagen genes, while the two other groups were strains of "knockout" mice
developed by Paolo Bonaldo, University of Padova, Italy. One group of mice
had both parents with the type VI collagen gene knocked out, while the other
group had only one parent without the gene. After six months, the
researchers removed chondrons to determine how they responded.

"We found significant osteoarthritic and developmental differences among
the three groups," Alexopoulos said. Specifically, 73 percent of the mice
with two knock-out parents showed evidence of mild to severe osteoarthritis.
This compared to 40 percent for mice with one knock-out parent and 13
percent for the control mice.

"These findings represent an important advance in our understanding of
osteoarthritis," Guilak said. "The study provides direct evidence of the
role of type VI collagen in the biomechanical properties of the PCM. While
the mechanism behind the accelerated development of osteoarthritis is not
yet clear, it suggests that the lack of type VI collagen negatively impacts
the ability of the cartilage to respond properly to the mechanical stresses
and pressures on the joint."

The experiments would not have been possible without the custom-built
"microaspirator," which could extract individual, intact chondrons. Other
methods of isolating chondrons, which either involve dissolving surrounding
tissues with harsh enzymes or grinding the cartilage in pieces, typically
yield damaged chondrons, Alexopoulos said.

"Using a tiny syringe, I was able to go across the surface of the
cartilage and vacuum up the chondrons without damaging them," Alexopoulos
said. "The chondrons literally popped out of the cartilage and into the
syringe. From that point, it was easy to analyze their structure."

It is estimated that more than 70 percent of Americans over the age of 65
show some signs of osteoarthritis, which is characterized by the slow
degeneration of the buffering layer of cartilage within joints. The other
major form of arthritis, rheumatoid arthritis, occurs when the body's immune
system attacks the linings of joints.

Guilak currently leads of group of clinicians and investigators from Duke
and the Durham VA Medical Center who are carrying out a broad range of basic
and clinical research into better understanding and treating osteoarthritis.
The effort is funded by grants from the National Institute on Aging (NIA)
and the National Institute of Arthritis and Musculoskeletal and Skin Disease
(NIAMS).

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