New research carried out on rodents reveals, for the first time, that preventing the loss of a molecule that is important for cartilage maintenance could delay the onset of osteoarthritis, a disease of the joints that causes disability and affects millions of people in the United States.
Osteoarthritis (OA) – also referred to as degenerative joint disease – is the most common form of arthritis, a general term used to describe a range of conditions that cause pain or disease in the joints.
The new study, led by the NYU Langone Medical Center in New York and published in the journal Nature Communications, shows that injecting the vital cell molecule adenosine into the joints can prevent OA in rat models of the disease.
OA most commonly affects the hips, hands, and knees, and it results from the gradual wear and tear of the cartilage that cushions the ends of the bones in the joint and stops them rubbing against each other.
The degeneration of cartilage in OA progresses slowly and, as time goes by, the joint swells and becomes painful and stiff. In some cases, OA can reduce function and disable a person so much that they cannot lead a normal life.
In fact, the condition can become so disabling – particularly when the knee or hip is affected – that there may be a need for surgery to replace the joint.
The new study concerns various activities of a molecule called adenosine that is essential for cell function and, as the research reveals, is also important for maintaining cartilage.
Cartilage comes from substances secreted by cells called chondrocytes. Having a regular supply of healthy chondrocytes is essential for producing and maintaining cartilage.
The researchers investigated the role that adenosine plays in maintaining a healthy supply of chondrocytes.
- OA affects 30 million adults in the U.S.
- The risk of developing the joint disease rises with age.
- It is more common in women than in men, especially after the age of 50.
They note in their study paper that adenosine levels inside and outside cells are “tightly controlled” by cellular stress, oxygen consumption, and the workings of mitochondria – the pockets inside cells that produce the energy for the cell.
Mitochondria supply the cell with energy in the form of chemical units called adenosine triphosphate (ATP), and adenosine is a byproduct of ATP metabolism.
It was already known that aging and inflammation reduces ATP production in chondrocytes, which in turn reduces levels of adenosine. However, until this study, it was not clear how that might relate to OA.
One of the main discoveries of the study is that reduction in chondrocytes, and therefore greater risk for OA, is driven not only by lower levels of adenosine surrounding the cells, but also by loss of signal-receiving proteins called adenosine A2A receptors on the surface of the cells.
If a chondrocyte has no A2A receptors, then it cannot pass the signals from the adenosine molecules surrounding them to their internal machinery. Loss of such signals impairs the cell’s ability to maintain cartilage.
The researchers found that mice lacking A2A receptors could not walk as easily as mice with the receptors. On closer examination, they also found OA in the knees of the mice without A2A receptors.
Curiously, the team also found that chondrocytes of rats with OA had raised levels of A2A receptors. They suggest that this is because of a “failed attempt” to make up for the loss of adenosine caused by inflammation-induced changes in ATP metabolism.
When they examined tissue samples of patients who had received replacement joints at NYU Langone because of OA, the researchers found that their chondrocytes also had higher levels of adenosine A2A receptors.
Probing further into the link with ATP metabolism, the team treated mouse chondrocytes with IL-1beta – a molecule that promotes OA. They found that the inflamed chondrocytes produced 39 percent less ATP and showed an 80 percent reduction in a molecule that transports ATP.
The team then showed that reducing adenosine levels by removing the enzyme that allows it to be produced from ATP led to OA in mice. It is known that humans who do not have this enzyme also develop OA.
The researchers also showed that injecting adenosine into the joints of rats with anterior cruciate ligament – a cause of OA in humans – prevented the animals from developing OA.
Senior investigator Bruce Cronstein, a professor of medicine at NYU Langone, says that the study “suggests that diminished ATP and adenosine production are likely contributing factors to the development of osteoarthritis in aging individuals.”
He adds that should their findings lead to successful therapies, then they could delay, and perhaps even prevent, the need for the million or so joint replacements that are carried out in the U.S. every year. He also notes that:
“Because joints may have to be replaced again and again, if we can put off the need for joint replacement until later in life, odds are that patients will only have to have this done once.”