Matrilin-3 gene discovered to prevent onset of osteoarthritis

Researchers develop animal model to study causes of arthritis

Providence, RI -- A gene that is associated with osteoarthritis and skeletal deformities in people has been shown to be responsible for preventing the onset of osteoarthritis in adult mice, according to a recent study led by Rhode Island Hospital. The matrilin-3 gene plays a role in early bone development, controls bone mineral density in adulthood and prevents osteoarthritis later in life.

Mutations in matrilin-3 have previously been linked to certain skeletal disorders and hand osteoarthritis. But this study, reported in the cover article of the August issue of the American Journal of Pathology, is the first to demonstrate that the loss of the gene leads to osteoarthritis, a joint disease that is caused by deterioration of cartilage, and usually occurs later in life.

"Clearly there is a correlation between matrilin-3 and osteoarthritis. Potentially, we could use it as a diagnostic tool or to predict whether someone is likely to develop osteoarthritis," says senior author Qian Chen, PhD, director of cell and molecular biology, and head of orthopaedic biology research at Rhode Island Hospital.

Chen is also a professor of medical science, and holds the Michael G. Ehrlich Chair in Orthopaedic Research, both at Brown Medical School.

The research has also led to an animal model that can be used to study the development of arthritis in real time, Chen says. Previous research has attempted to pinpoint causes of osteoarthritis through other means, such as looking retrospectively at the causes of the disease or inflicting an injury on a joint to mimic a sports injury or trauma.

"In the long term, it helps us understand the mechanism of human osteoarthritis development. Very few molecules have even been associated with osteoarthritis, so this is a huge deal. Now that matrilin-3 has been clearly shown to develop osteoarthritis in an animal model, we can study it further," Chen says.

There are four matrilins, or proteins, that form the extracellular matrix (ECM), which holds cartilage together. Matrilin-1 and -3 are specific to skeleton tissues, while matrilin-2 and -4 are also found in other tissues throughout the body. There has been a link between mutated forms of matrilin-3 and hand osteoarthritis, as well as skeletal disorders such as multiple epiphyseal dysplasia (MED), a disorder that begins in childhood and can include malformation of the hands, feet and knees and abnormal curvature of the spine.

In this study, researchers knocked out matrilin-1 and -3 in mice in order to study their link to osteoarthritis. When matrilin-1 was knocked out, there was no apparent effect. When matrilin-3 was removed, the mice had a normal and fertile lifespan and appeared to have normal skeletal development.

However, without matrilin-3, researchers noticed that during embryonic development, mice developed premature and extended hypertrophy the phase when cells increase in size to form bone. Later in life, those mice had higher bone mineral density (BMD) and higher rates of osteoarthritis. In people, BMD is a hallmark of certain forms of osteoarthritis.

Compared with mice whose genes had not been altered, the mice lacking matrilin-3 showed significantly higher BMD both in the knee joint and throughout the body at 18 weeks of age, the time when mice typically reach peak bone density. Clinical studies in humans have shown that the prevalence of knee and hip osteoarthritis increases with increasing BMD.

"Our study reveals an unexpected property of matrilin-3 in maintaining proper BMD, a factor that was not previously examined," the authors write. "However, the mechanism of the association between increased bone density and joint degeneration is not known. Our data show that matrilin-3 deficiency results in both the increase of BMD and joint cartilage degeneration, thereby connecting these two events together."

Researchers could not make the connection, however, between a lack of matrilin-3 and skeletal disorders, such as MED. The mice lacking matrilin-3 developed a higher incidence of osteoarthritis in adulthood without developing deformities in childhood.

The results challenge one theory of osteoarthritis that the disease is caused by degeneration from an abnormal skeletal structure.

"Our study shows that even in those normal looking skeletons, you still develop osteoarthritis. So there's not necessarily a link between those two," Chen says. "Maybe there's something else that causes it, such as stiff bone."

Osteoarthritis affects more than 20 million Americans and is the most common type of arthritis. It is characterized by a breakdown in cartilage, commonly affecting the knees, hips and lower back. While younger people can develop osteoarthritis from joint injuries, the disease most often occurs in people over 65. The causes of osteoarthritis are not known, but they are believed to be both genetic and environmental such as being overweight or suffering sports injuries.

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Other authors on the paper are: Louise van der Weyden, Allan Bradley and David J. Adams, all of the Wellcome Trust Sanger Institute, Cambridge, UK; Lei Wei, Junming Luo and Xu Yang, all of Rhode Island Hospital and Brown Medical School; and David E. Birk of Thomas Jefferson University, Philadelphia.

This study was supported by a CJ Martin/RG Menzies Fellowship and a CJ Martin Fellowship from the National Health and Medical Research Council of Australia, by the National Institutes of Health and by the Arthritis Foundation.

Founded in 1863, Rhode Island Hospital (www.rhodeislandhospital.org) is a private, not-for-profit hospital and is the largest teaching hospital of Brown Medical School. A major trauma center for southeastern New England, the hospital is dedicated to being on the cutting edge of medicine and research. Rhode Island Hospital ranks 13th among independent hospitals who receive funding from the National Institutes of Health, with research awards of more than $27 million annually. Many of its physicians are recognized as leaders in their respective fields of oncology, cardiology, orthopedics and minimally invasive surgery. The hospital's pediatrics wing, Hasbro Children's Hospital, has pioneered numerous procedures and is at the forefront of fetal surgery, orthopedics and pediatric neurosurgery.


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