A molecule previously linked to diabetes, cancer, and muscle atrophy appears to also be involved in the development of osteoarthritis, and may be a useful treatment target, new research with mice shows.
Osteoarthritis is one of the most common problems associated with aging, and although therapies exist to treat the pain that results from the breakdown of the cartilage that cushions joints, there are no available therapies to modify the course of the disease.
When researchers knocked out the gene FoxO1 in mice, the animals developed osteoarthritis. But when the researchers increased the levels of the FoxO1 molecule in mice developing osteoarthritis, the animals exhibited less cartilage damage.
The study appears in the Proceedings of the National Academy of Sciences.
“Osteoarthritis, or joint degeneration, is a disease that affects more than 32 million people in the US alone but that does not have a medical therapy to alter its progression,” says senior investigator Regis J. O’Keefe, professor of orthopaedic surgery and head of the department of orthopaedic surgery at Washington University in St. Louis.
“A better understanding of the fundamental processes involved in osteoarthritis and the degeneration of cartilage is required if we’re going to be more successful in treating this very common and very expensive disorder,” O’Keefe says.
Commonly, O’Keefe says, people with osteoarthritis have suffered knee injuries that damaged the knee’s meniscus. Over time, arthritis then can develop in the joint.
“Unlike skin or bone or other organs that can regenerate in response to injury, cartilage has very little regenerative potential,” O’Keefe says.
However, when the mice in these experiments had elevated levels of the FoxO1 molecule, osteoarthritis’s progress slowed or even reversed. The researchers believe the molecule enhances a process called autophagy in the arthritic joint to interfere with cartilage damage and the development of arthritis. Autophagy is the body’s way of clearing out damaged tissue.
In these experiments, the researchers found that autophagy was disrupted in the mice with reduced levels of FoxO1 and that the process was enhanced in animals with higher levels of the molecule.
“In other words, maintaining a higher level of autophagy seemed to be beneficial to maintaining these cartilage cells and, thus, maintaining a healthy knee joint,” says co-corresponding author Jie Shen, assistant professor of orthopedic surgery.
The findings raise the possibility of delivering FoxO1 to arthritic joints through nanotechnology as a way to regulate autophagy and keep joints healthier, O’Keefe says.
“In mice with injuries that typically progress to become osteoarthritis, the knee joints still appear normal about a week after injury,” O’Keefe explains. “But when we measure autophagy in the cartilage after injury to those same knee joints, although the joints themselves look fine, the autophagy process already is shut off. The injury completely turns it off, and once autophagy is off, the cartilage begins to degenerate.”
If FoxO1 can alter that process in people, protecting cartilage from damage as it does in mice, it eventually may be possible to prevent or delay millions of future knee and hip replacement surgeries, he says.
The National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health supported the work.
