Scientists discover hidden trigger behind achilles pain and tennis elbow

"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 disorders as tendinopathies. They are among the most common problems treated by orthopedic specialists, yet effective therapies remain limited. Physical therapy can provide relief, but in many severe cases it offers only modest improvement. Because of this, researchers have been searching for a clearer understanding of what actually drives tendon disease in hopes of developing better treatments.

HIF1 Protein Identified as a Molecular Cause

A research team led by Snedeker and Katrien De Bock, professor of exercise and health at ETH Zurich, has now uncovered a key piece of the puzzle. They identified a protein called HIF1 as a central driver of tendon disease. Part of HIF1 functions as a transcription factor, meaning it regulates the activity of specific genes inside cells.

Previous studies had found elevated levels of HIF1 in damaged tendons, but scientists did not know whether the protein was merely associated with disease or directly responsible for it. Through experiments in mice and studies of human tendon tissue, the team demonstrated that HIF1 is not just present during disease but actively triggers it.

Experiments Show Direct Link to Tendon Damage

In their mouse studies, researchers either kept HIF1 permanently switched on or completely turned it off. Mice with constantly activated HIF1 developed tendon disease even without excessive strain. In contrast, mice in which HIF1 was deactivated in tendon tissue did not develop tendon disease, even when their tendons were overloaded.

The team also studied human tendon cells collected during tendon surgeries at the hospital. In both mice and human tissue samples, higher levels of HIF1 caused harmful structural changes in the tendons. Specifically, more crosslinks formed within the collagen fibers that provide tendons with their strength and structure.

"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. The researchers also observed increased growth of blood vessels and nerves into the tendon tissue. "This could be the explanation for the pain commonly observed in tendinopathy," says Moschini.

Why Early Treatment Matters

"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 highlights young athletes in particular, since they often experience tendinopathies while their condition may still be manageable.

Over time, however, damage linked to HIF1 can build up and eventually become permanent. "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."

Searching for Targeted Tendon Treatments

Now that HIF1 has been identified as a molecular driver of tendon disease, an obvious question arises. Could drugs be developed to block HIF1 and prevent or reverse tendinopathy?

According to De Bock, the answer is complicated. HIF1 plays an important role throughout the body by sensing low oxygen levels (hypoxia) and triggering normal adaptive responses. "Switching HIF1 off throughout the body would likely lead to side effects," she says.

One possibility is finding ways to specifically reduce HIF1 activity only in tendon tissue. However, De Bock believes a more promising strategy may be to study the biological processes surrounding HIF1 in greater detail. By identifying other molecules influenced or controlled by HIF1, researchers may uncover safer and more precise targets for treating tendinopathy. That search is now underway.