Rodents with trouble walking reveal potential treatment approach for most common joint disease

May 11, 2017

Maintaining the supply of a molecule that helps to nourish cartilage prevented osteoarthritis in animal models of the disease, according to a report published in Nature Communications online May 11.

The study is the first, say its authors, to provide evidence that , a biochemical at the heart of human cellular function, plays another crucial role—keeping on hand a steady number of healthy chondrocytes, the cells that make and sustain cartilage.

Important to the study's implications, adenosine is derived from (ATP), the molecule that stores the energy needed by the body's cells until they break it up to use it. Scientists have known that both inflammation and aging lead to diminished ATP production (and so lower adenosine levels) in chondrocytes. Until now, they had not linked diminished adenosine levels to osteoarthritis, the commonplace, "wear-and-tear" form of arthritis.

Led by researchers at NYU Langone Medical Center, the study found that maintaining high levels of adenosine in rats with damage to the anterior cruciate ligament (ACL), which is known to lead to osteoarthritis in humans, prevented the rats from developing the disease. If the finding proves to be true in humans, the study authors say adenosine replacement therapy could potentially delay the onset of osteoarthritis and the need for joint replacements.

"We found that if adenosine levels decrease, or if the capacity to respond to adenosine diminishes, cartilage starts to degenerate," says study senior investigator Bruce Cronstein, MD, the Dr. Paul R. Esserman Professor of Medicine at NYU Langone. "Our study suggests that diminished ATP and adenosine production are likely contributing factors to the development of osteoarthritis in aging individuals," says Cronstein, who also serves as the director of the Clinical and Translational Science Institute (CTSI), and chief of the Division of Translational Medicine at NYU Langone.

The findings suggest that reductions in the number of cartilage-producing cells, and greater risk for osteoarthritis, may be driven not just by lower adenosine levels but also by lower levels of the protein on the surface of chondrocytes designed to receive and pass on adenosine's signal. Adenosine helps to sustain such cells by fitting into a protein called the A2A adenosine receptor on their surfaces, like a key into a lock. Cronstein and colleagues observed that mice lacking the A2A adenosine receptor did not move (walk) as easily or as well as mice with the receptor. Radiologic examination of the knees of mice without the receptor confirmed that they had osteoarthritis.

Cronstein and his team also found that levels of adenosine A2A receptors went up on rat chondrocytes when osteoarthritis was present, in what the researchers say was a "failed attempt" to compensate for the loss of adenosine from the energy-processing (metabolic) changes underlying the inflammation. Additional tests in tissue samples from osteoarthritic patients who had joint replacements at NYU Langone found similarly increased levels of adenosine A2A receptors on chondrocytes.

When researchers treated mouse chondrocytes with a molecule called IL-1beta, which contributes to the development of osteoarthritis, they found that 39 percent less ATP was produced by the inflamed chondrocytes. They also found 80 percent less expression of ANKH, a molecule that exports ATP, in the IL-1beta-treated cells. Finally, they found that lacking the enzyme involved in turning ATP into adenosine diminished adenosine levels, which led to osteoarthritis in mice. The lack of the enzyme in humans is also known to lead to the disease.

When the team administered adenosine packaged in lipid bubbles into rats' ACL injuries, researchers found that the excess adenosine, as mediated by the adenosine A2A receptor, prevented the development of in the animals.

Cronstein says related future therapies, if successful, would prevent or delay the need for some of the million or so joint replacements performed each year, numbers of which are growing in part thanks to obesity, which puts more pressure on joint structures.

"Because joints may have to be replaced again and again, if we can put off the need for until later in life, odds are that patients will only have to have this done once," says Cronstein.

Explore further: Scientists discover possible treatment to reduce scarring

More information: Nature Communications (2017). DOI: 10.1038/ncomms15019

Related Stories

Scientists discover possible treatment to reduce scarring

July 6, 2012
Whether from surgery or battle wounds, ugly scars can affect body and mind. Now a new research report appearing online in the FASEB Journal offers a new strategy to reduce or eliminate scars on the skin. Specifically, scientists ...

Researchers discover a new signaling pathway to combat excess body weight

October 16, 2014
The number of overweight persons is greatly increasing worldwide - and as a result is the risk of suffering a heart attack, stroke, diabetes or Alzheimer's disease. For this reason, many people dream of an efficient method ...

Arthritis cartilage shows mitochondrial dysfunction

November 19, 2012
(HealthDay)—Cartilage from osteoarthritis patients shows greater oxidative damage and mitochondrial dysfunction than healthy cartilage, which is associated with the downregulation of the superoxide dismutase 2 (SOD2) gene, ...

Loss of enzyme promotes tumor progression in endometrial cancer

December 7, 2015
Scientists have shown for the first time why loss of the enzyme CD73 in human cancer promotes tumor progression.

Caffeine may block inflammation linked to mild cognitive impairment

October 9, 2012
Recent studies have linked caffeine consumption to a reduced risk of Alzheimer's disease, and a new University of Illinois study may be able to explain how this happens.

Recommended for you

US arthritis prevalence is much higher than current estimates

November 27, 2017
New research indicates that the prevalence of arthritis in the United States has been substantially underestimated, especially among adults

Maintaining sufficient vitamin D levels may help to prevent rheumatoid arthritis

November 20, 2017
Maintaining sufficient vitamin D levels may help to prevent the onset of inflammatory diseases like rheumatoid arthritis, research led by the University of Birmingham has discovered.

Old World monkeys could be key to a new, powerful rheumatoid arthritis therapy

November 16, 2017
In the quest for a new and more effective treatment for rheumatoid arthritis, researchers from the Keck School of Medicine of USC looked to a primate that mostly roams the land in Asia, the Middle East and Africa. It was ...

Study lists foods for fighting rheumatoid arthritis symptoms and progression

November 8, 2017
A list of food items with proven beneficial effects on the progression and symptoms of rheumatoid arthritis is provided in a new study published today in Frontiers in Nutrition. The authors suggest incorporating these foods ...

Prototype equipment can detect rheumatoid arthritis

September 28, 2017
According to a first clinical study published in the scientific journal Photoacoustics, the University of Twente and various European partners have designed a device that shows the difference between healthy fingers and arthritic ...

Improving the recognition of anxiety and depression in rheumatoid arthritis

August 28, 2017
A study conducted by Keele University shows that patients with rheumatoid arthritis who are also suffering with anxiety or depression may avoid talking to their GP about their mental health symptoms.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.