Investigators unveil genetic links into how osteoarthritis destroys cartilage

A team of orthopedic researchers from the University of Rochester Medical Center in New York reported what they say is 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 in the Journal of Bone and Mineral Research.

The findings serve as an important foundation for the design of new treatments for osteoarthritis (OA), the researchers said in a University of Rochester Medical Center press release.

Prior to this study, researchers knew little about the cellular and molecular events that cause cartilage to break down in osteoarthritic joints. Past studies had suggested that higher levels of a key signaling protein, beta-catenin, were connected to osteoarthritis, but there was no direct evidence to confirm it, or to suggest its role, according to the press release.

In this recent trial, 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 patients with OA.

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, according to the press release.

“We have created … the first model in a living animal that shows exactly how osteoarthritis causes damage,” Di Chen, MD, PhD, associate professor in Rochester’s department of orthopedics and lead author of the study, said in the press release. “That, of course, puts us in position to interfere with the processes that contribute to the damage in a new and powerful way.”

In their investigation, researchers administered tamoxifen to increase beta-catenin production in 3- and 6-month-old conditional-activation mice. Researchers then examined the articular cartilage tissues 2 months later to look for structural and morphological changes.

They found severe destruction in the articular cartilage of 8-month-old beta-catenin cAct mice. Even at the molecular level, the joints of the study mice mimicked those seen in human patients with OA, according to the press release.

Chen said physiological responses in the study mice that were intended to heal the joint actually contributed to the disease by mistakenly forming bone where cartilage should be, resulting in misguided cell growth. Control mice without high levels of beta-catenin expression experienced no damage to their cartilage.

Further analysis found that too much beta-catenin signaled for higher production of an enzyme, matrix metalloproteinase 13 (MMP-13), known to preferentially break down and destroy the type-2 collagen that makes up 90% of articular cartilage, according to the press release.

In addition, higher beta-catenin levels were found to produce a nearly sixfold increase in expression versus controls of the gene for bone morphogenetic protein-2 (BMP-2) in the mice.

Chen’s team is 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, he said.

“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.”