Lack of specific collagen type leads to osteoarthritis

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Public release date: 20-Feb-2005

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Duke University Medical Center

Lack of specific collagen type leads to osteoarthritis

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

opoulos, Ph.D., developed a novel " micro-vacuuming " technique. With this

device, opoulos 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.

opoulos 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. opoulos, 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, " opoulos

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, " opoulos 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, " opoulos 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, opoulos said.

" Using a tiny syringe, I was able to go across the surface of the cartilage

and vacuum up the chondrons without damaging them, " opoulos 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).

http://www.eurekalert.org/pub_releases/2005-02/dumc-los021505.php