By Eth Zurich

Scientists have uncovered a molecular trigger behind common overuse tendon injuries, revealing that HIF1 directly drives disease progression.

Painful problems such as Achilles tendon pain, tennis elbow, swimmer’s shoulder, and jumper’s knee affect both young athletes and older adults. Despite their different names and locations, these injuries share a common cause: repeated strain on tendons that leaves them inflamed and often severely painful.

“Tendons are fundamentally susceptible to overuse,” explains Jess Snedeker, a professor of orthopaedic biomechanics at ETH Zurich and Balgrist University Hospital in Zurich. “They must withstand powerful loads, with all the forces of our muscles being concentrated to the relatively thin tendons that transmit these forces into movement of our skeleton.”

Doctors refer to these conditions collectively as tendinopathies. They are among the most common reasons people seek care from orthopedic specialists, yet there are few effective treatment options. Physiotherapy can provide relief in some cases, but for many patients with more advanced disease, it offers only limited benefit. This gap has driven researchers to investigate tendon injuries more deeply in hopes of finding better therapies.

Not just correlation – causation

A research team led by Snedeker and Katrien De Bock, professor of exercise and health at ETH Zurich, has now made a significant breakthrough. The scientists identified the protein HIF1 as a key molecular factor that actively drives the development of tendon disease. Part of HIF1 functions as a transcription factor, meaning it regulates how certain genes are switched on or off inside cells.

Previous studies had shown that HIF1 levels are higher in damaged tendons, but it was not clear whether this increase was merely associated with the disease or if it actually caused it. Using experiments in mice and analyses of human tendon tissue, the researchers demonstrated that HIF1 directly triggers the pathological changes seen in tendinopathy.

Treatment before it is too late

In their animal studies, the team either kept HIF1 permanently active or completely disabled it in tendon tissue. Mice with constantly active HIF1 developed tendon disease even without excessive strain. In contrast, mice in which HIF1 was turned off did not develop tendon problems, even when their tendons were subjected to heavy loading.

Similar results were seen in experiments using human tendon cells taken from surgical procedures at the hospital. In both models, high levels of HIF1 caused harmful remodeling of tendon tissue: More crosslinks formed within the collagen fibers that make up the basic structure of the tendons.

“This makes the tendons more brittle and impairs their mechanical function,” explains Greta Moschini, a doctoral student in De Bock and Snedeker’s groups and lead author of the study. In addition, blood vessels and nerves growth into the tendon tissue. “This could be the explanation for the pain commonly observed in tendinopathy,” says Moschini.

“Our study not only provides new insight into how the disease develops. It also shows that it’s important to treat tendon problems early,” says Snedeker. He is thinking particularly of young athletes, who frequently struggle with tendinopathies. In these cases, it is often still possible to treat the problems. “However, the damage caused by HIF1 in tendon tissue can accumulate and become irreversible over time. Physiotherapy then no longer helps, and the only treatment at this moment is to surgically remove the diseased tendon.”

A starting point to search for treatments

The fact that HIF1 has now been identified as a molecular driver raises the question whether it is possible to develop medicines that deactivate HIF1 and therefore can prevent or cure tendon disease. It is not quite that easy, explains ETH Professor De Bock. In many organs of the body, HIF1 is responsible for detecting a lack of oxygen (hypoxia) and activating a physiological adaptation. “Switching HIF1 off throughout the body would likely lead to side effects,” she says.

It may be possible to look for methods that specifically deactivate HIF1 only in the tendon tissue. In De Bock’s view, however, the more promising approach would be to explore the biochemical processes around HIF1 in the cells in greater detail. This could help to identify other molecules that are influenced or controlled by HIF1 and that could be more suitable targets for the treatment of tendinopathy. The researchers will now embark on precisely that search.