Researchers have identified the HIF1 protein as a key factor in tendon pain, a condition that affects both athletes and older adults. Overuse of tendons can lead to medical issues such as Achilles tendon pain, tennis elbow, swimmer's shoulder, and jumper's knee. These conditions are known as tendinopathies and are common reasons for visits to orthopedic specialists.
Current treatments for tendinopathies are limited. While physiotherapy can be helpful, it does not work for all patients, especially those with severe cases. As a result, scientists continue to study these problems in hopes of finding more effective therapies.
A research team led by Snedeker and Katrien De Bock, professor at ETH Zurich, has discovered that HIF1 acts as a central molecular driver of tendon disease. The protein functions as a transcription factor controlling gene activity within cells. Although high levels of HIF1 had previously been found in diseased tendons, it was unclear if this was a cause or simply an effect of the disease.
Through experiments on mice and human tendon tissue collected from surgeries, researchers demonstrated that increased HIF1 directly leads to changes in tendon structure. In their mouse studies, they activated HIF1 permanently or deactivated it entirely. Mice with constantly active HIF1 developed tendon disease even without overloading the tendons. Conversely, when HIF1 was turned off in the tendons—even under overload—no disease occurred.
The experiments also showed that higher levels of HIF1 resulted in more crosslinks forming within collagen fibers—the main structural component of tendons—which makes them more brittle and reduces their mechanical function.
"This makes the tendons more brittle and impairs their mechanical function," said Greta Moschini, doctoral student in De Bock and Snedeker’s groups and lead author of the study. Blood vessels and nerves were also found growing into the affected tendon tissue. "This could be the explanation for the pain commonly observed in tendinopathy," Moschini added.
"Our study not only provides new insight into how the disease develops. It also shows that it's important to treat tendon problems early," said Snedeker. He pointed out that young athletes often face these issues but may still benefit from early treatment: "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."
With HIF1 now identified as a molecular driver of these conditions, there is interest in developing drugs targeting this protein to prevent or cure tendon diseases. However, Professor De Bock noted challenges: since HIF1 helps organs respond to low oxygen levels throughout the body (a process called hypoxia), shutting down its activity everywhere could produce unwanted side effects.
De Bock suggested another direction: "Switching HIF1 off throughout the body would likely lead to side effects." Instead of targeting HIF1 directly across all tissues, she recommended investigating related biochemical pathways within cells to find other molecules influenced by or controlled by HIF1 which might serve as better drug targets for treating tendinopathy.
The research team plans further studies focused on identifying such alternative targets.
