A team of orthopedic researchers has found definitive, genetic proof of how the most common form of arthritis destroys joint cartilage in nearly 21 million aging Americans, according to a study published online September 2 in the Journal of Bone and Mineral Research. The findings serve as an important foundation for the design of new treatments for osteoarthritis (OA), researchers said.
Going into the study, little was known about the cellular and molecular events that cause cartilage to break down in osteoarthritic joints. Past studies had suggested that higher levels of beta-catenin, a key signaling protein, were connected to OA, but there was no direct evidence to confirm it, or to suggest its role. The study provides both.
Researchers genetically engineered adult mice to have high levels of beta-catenin, and saw that they lost most of their articular cartilage, the protective layer that covers the ends of bones within joints. The mice also developed the same bony growths and microfractures seen in the joints of human OA patients. A companion experiment on human cartilage cells taken from patients with severe arthritis also confirmed that their beta-catenin levels were much higher than normal.
OA gradually destroys all cartilage in joints while forming scar tissue and painful, bony growths. Advanced cases bring deformity and severe pain as patients loose the protective cushion between bones in weight-bearing joints like knees and hips. Until the late 1980s, OA was regarded as part of growing old. Since then, studies have revealed that biochemical changes contribute to the disease that might be reversed by drugs. Current medications, NSAIDs and Cox 2 inhibitors, are used to reduce symptoms in patients with mild cases, and joint replacement surgery for severe cases. Few options exist for those in between.
Research teams from Oxford, and from Leiden University in The Netherlands, published the results of gene-mapping studies in 2004 and 2005 that found people with an extremely rare genetic mutation were much more likely to develop OA. The mutation was in the frzb (Frisbee) gene, known to code for a protein called sFRP3 that normally keeps beta-catenin levels in check. This link between the frzb mutation, beta-catenin and osteoarthritis was still a hot topic last November at the annual meeting of American College of Rheumatology in Boston. When Di Chen, MD, PhD, associate professor in the department of Orthopaedics, University of Rochester Medical Center, and lead author of the study, heard about it from returning colleagues, he joined the race to provide the first direct, genetic evidence in a live, adult mouse that raising beta-catenin levels creates the same effects as OA in aging human joints.
While the original gene-mapping studies provided clues about the causes of OA, they also created mystery. The frzb gene mutation found to cause a rise in beta-catenin is extremely rare, but tens of millions of people develop OA as they age. Something beside the frzb mutation must be causing most cases. One theory has it that the mechanical force created by the weight of the body on joints over time is converted into ever stronger biochemical signals for more beta-catenin. While the force applied to joints cannot be reduced (except by weight loss), destructive signals sent in response to that force might be shut down by future drugs.
Another theory proceeds from the fact that patients with injuries to the meniscus, the sponge-like layer of cartilage that sits between the bones of the knee, are much more likely to develop OA in the ensuing years. Could the deteriorating meniscus be signaling nearby articular cartilage to raise beta-catenin levels?
Chen’s team has studies underway looking at whether meniscal injuries or biochemical reactions to mechanical force cause beta-catenin levels to rise. Other studies are already examining exactly how beta-catenin signaling changes levels of BMP-2 and MMP-13 in articular cartilage cells.
Along with Chen, Mei Zhu, Qiuqian Wu, Mo Chen, Chao Xie, Randy Rosier, Regis O’Keefe, and Michael Zuscik led the work within the Department of Orthopaedics and Center within the University of Rochester School of Medicine and Dentistry, Rochester, NY. Dezhi Tang led the effort at the Spine Research Institute at Shanghai University of Traditional Chinese Medicine in Shanghai, China, as did Suyang Hao in the Department of Pathology at the University of Massachusetts Memorial Medical Center. The work was supported by the National Institutes of Health.
"The first step was to prove that beta-catenin is central to OA development, and I think we have done that," Chen said. "Now we are seeking to confirm that mechanical loading and mensical injury create higher levels of beta-catenin in osteoarthritic joints, and that this in turn causes cartilage destruction and too fast differentiation of cartilage into bone."
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[Source: Eureka Alert]