Urocortin molecule prevents cell death in osteoarthritis

Knee pain
Professor Paul Townsend
Professor Paul Townsend
The findings of a new study suggest that the urocortin protein could be used both to prevent and to treat osteoarthritis…

Researchers have discovered that the naturally occurring molecule urocortin guards against cell death associated with osteoarthritis.

Scientists from the University of Manchester and the University of Westminster, whose findings have been published in the journal Cell Death & Disease, believe that the protein could be used in the development of novel medicines to prevent joint degradation. There is even evidence to suggest that urocortin could help to stimulate new cell growth within patients who already suffer from osteoarthritis.

At present, it’s difficult to predict how people’s osteoarthritis will develop and how they are likely to respond to treatment. One thing that we do know is that if we administer urocortin before any damage has occurred, it operates in a preventative manner.
Professor Paul Townsend
Osteoarthritis is characterised by the destruction and loss of cartilage around a person’s joints. The condition, which currently affects around one million people in the United Kingdom annually, can lead to reduced joint mobility in the knees, hips, hands and vertebrae. As the ageing population continues to grow, so too will the prevalence of the disease.

The ability to effectively treat osteoarthritis, therefore, could result in significant benefits both for healthcare budgets and for patients’ quality of life. To learn more about urocortin’s potential within this field, I spoke to joint lead researcher of the study Professor Paul Townsend from the University of Manchester’s Institute of Cancer Sciences.

'Cells are damaging themselves'


"The damage caused by osteoarthritis results from what we call an inflammatory response," he began. "Essentially, the cells within the affected joint become hyperactive. I find that it helps to think of the joint as if it were an organ; in order to operate effectively, it must remain carefully balanced and controlled. When a person has osteoarthritis, the cartilage cells and the chondrocytes initiate an unwanted autoimmune response. In a way, the body is damaging itself."

Chondrocytes are cells responsible for producing and maintaining healthy cartilage in a person’s joints. Osteoarthritis involves the production of programmed chemicals which kill these cells. Consequently, those suffering from the disease have fewer active chondrocytes than individuals with healthy joints.

During the course of their research, Professor Townsend and his co-author Dr Ian Locke from the University of Westminster found that urocortin prevents chemically induced chondrocyte death. Surprisingly, this discovery was – to a certain extent – unintended.

Accidental discovery


"I’ve been working with urocortin for around 15 years," explained Professor Townsend. "This molecule is a natural peptide thought to exist and operate exclusively within the brain. It is what we call a ‘neuropeptide’, and purified versions have curious effects on cells. For example, urocortin is able to stop certain cells from dying.

"Initially, we were looking at the heart," he continued. "The heart is an interesting organ in the sense that cells that die there don’t get replaced. We wanted to devise a way to protect the heart against cardiac arrest, coronary artery disease, etc. It was only by chance that we discovered that urocortin has protective properties for cartilage as well."

The scientists not only uncovered urocortin’s potential to protect joint cells against death. They also succeeded in learning a great deal about the mechanisms involved in this process.

'Locks and keys'


"Urocortin peptides operate in a similar manner to locks and keys," explained Professor Townsend. "Depending on which lock is present and which key is available, you get a different biological response. Typically, these biological responses involve growth; cellular proliferation whereby cells divide and multiply. This proliferation is controlled by a number of chemical processes that fall under the banner of ‘signal transduction’.

"The mitogen-activated protein kinase (MAP kinase) is an extremely important example of signal transduction," he continued. "It is the process by which the enzyme ERK1 turns one molecule into another. Our research shows that urocortin can directly inhibit the effects of ERK1, thus controlling its levels."

The ability to control cellular proliferation could facilitate the development of new medicines capable of preventing joint degradation. I went on to ask how such medicines might be prescribed. Are they likely to be administered only to patients at high risk of osteoarthritis, or could they achieve wider applications?

'Urocortin could still be improved'


"Honestly, how long is a piece of string?" asked Professor Townsend. "At present, it’s difficult to predict how people’s osteoarthritis will develop and how they are likely to respond to treatment. One thing that we do know is that if we administer urocortin before any damage has occurred, it operates in a preventative manner. However, whilst Mother Nature has done a damn good job, urocortin could still be improved.

"It has some really interesting biological effects," he continued. "If you administer too much, for example, it can lead to excessive lowering of blood pressure. That’s fine; it can be of use in certain cases, but you wouldn’t want to prescribe it to a person prone to fainting. Basically, we need to ‘dial in’ the pro-urocortin activity and ‘dial out’ any unwanted side effects."

One of the study’s most exciting implications is the potential of urocortin to treat, as well as to prevent, osteoarthritis and joint degradation more generally.

"We actually found that the peptide stimulates the formation of bone-forming and protective cells," said Professor Townsend. "Interestingly, we also discovered that when it comes to other osteoporotic bone diseases, urocortin inhibits osteoclasts: cells that are instrumental in joint degradation."

Next steps


My final question concerned the next steps for this research project. I asked how the effects of urocortin are likely to translate across to human models. As Professor Townsend explained, things look particularly promising in this respect.

"Our previous research was conducted using human cell lines and other applicable models," he concluded. "We are now applying our method to real patients. Since moving our lab to Manchester, we have gained access to human osteoarthritic material. Fortunately, urocortin appears to have exactly the same effect in humans as it did in previous models; it translates perfectly. We know that we’re following the right path."


If you’d like to learn more about the potential medical applications of urocortin, check out the full paper: ‘Urocortin protects chondrocytes from NO-induced apoptosis: a future therapy for osteoarthritis?’

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Would the osteoarthritis caused by ankylosing spondylitis also benefit from Urocortin?

Shashank - India
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