Researchers at ETH Zurich report that hypoxia-inducible factor 1 (HIF1) can actively drive harmful tendon changes linked to conditions such as Achilles tendon pain and tennis elbow. In mouse models and in human tendon cells collected during surgery, elevated HIF1 was associated with pathological remodeling that made tendon tissue more brittle and was accompanied by neurovascular ingrowth that may help explain pain.
Tendinopathies—an umbrella term doctors use for chronic, painful tendon disorders—include Achilles tendon pain, tennis elbow, swimmer’s shoulder and jumper’s knee. They can affect both young athletes and older adults, and are often associated with repeated strain and overload.
“Tendons are fundamentally susceptible to overuse,” said Jess Snedeker, a professor of orthopaedic biomechanics at ETH Zurich and Balgrist University Hospital in Zurich. Snedeker noted that tendons must transmit high muscle forces through comparatively thin connective tissue structures.
In a study published in Science Translational Medicine, Snedeker and Katrien De Bock, a professor of exercise and health at ETH Zurich, and their colleagues focused on hypoxia-inducible factor 1 (HIF1), a protein complex involved in cellular responses to low oxygen. Part of HIF1 functions as a transcription factor that regulates gene activity.
Previous research had reported elevated HIF1 in diseased tendons, but whether it was merely associated with injury or directly contributed to disease was unclear. The ETH Zurich team reported evidence supporting a causal role: in mouse experiments, animals with persistently activated HIF1 developed tendon disease even without excessive mechanical strain, while deactivating HIF1 in tendon tissue protected mice from developing tendon disease even when the tendons were overloaded.
The researchers also analyzed human tendon cells obtained during tendon surgeries. They reported that higher HIF1 activity coincided with structural changes in tendon tissue, including increased crosslinking within collagen fibers.
“This makes the tendons more brittle and impairs their mechanical function,” said Greta Moschini, a doctoral student in De Bock and Snedeker’s groups and the study’s lead author. The team also observed increased growth of blood vessels and nerves into tendon tissue; Moschini said this neurovascular ingrowth “could be the explanation for the pain commonly observed in tendinopathy.”
Snedeker said the findings underscore the importance of addressing tendon problems early, particularly in young athletes. He said damage linked to HIF1 activity can accumulate and, over time, become irreversible—at which point physiotherapy may no longer help and surgical removal of diseased tendon tissue may be the remaining option.
De Bock cautioned that directly switching off HIF1 throughout the body could cause side effects because of its broader role in oxygen sensing. Instead, the researchers said they are exploring the molecular pathways downstream of HIF1 to identify more targeted approaches that could be safer for treating tendinopathy.
