ZJU scientists unveil the enigma of the vulnerability of Achilles tendon

In the human body, there is a soft spot- Achilles tendon. As its name suggests, the Achilles tendon is one of the most powerful and fragile tendons in the body. The Achilles tendon can endure a load close to 8 times the body weight during exercise, making it extremely vulnerable to injury. Furthermore, due to the unique nature of tendons, failing to consult a doctor soon after an injury can lead to chronic tendon disease, which is characterized by pain, swelling, and movement problems. Tendo heterotopic ossification (HO) is a special type of chronic tendon disease, that is, the bone grows in soft tissue (tendon) where it normally doesn’t exist, further destroying the morphological structure and function of the tendon tissue. Famous athletes such as LIU Xiang and Kobe Bryant had to retire early from sports due to a lack of a radical solution for Achilles tendon injuries.

Using single-cell sequencing technology, Prof. OUYANG Hongwei from the ZJU_UoE Institute led his team to reveal that tissue microenvironment changes during tendon heterotopic ossification alters gene expression and cell fate determination of tendon stem progenitor cells, demonstrating that this process can be blocked by small molecule inhibitor BIBF1120. These findings were published in Bone Research, providing a novel treatment for tendon heterotopic ossification.

The researchers firstly found that the tendon specific transcription factor MKX decreased significantly in heterotopic ossified human tendon, and knockout of Mkx led to spontaneous ossification of mouse tendon, suggesting that MKX plays a critical role in heterotopic ossification of tendon.

Heterotopic ossification of tendon caused by decreased MKX expression or Mkx knockout

Further studies revealed that Mkx knockout mouse tendon cells expressed high levels of angiogenesis related genes, resulting in vascular invasion and tendon extracellular matrix microenvironment remodeling, and abnormal activation of osteogenic and chondrogenic differentiation related genes in tendon stem progenitor cells. These data indicated that inhibition of angiogenesis may improve the tendon tissue microenvironment and prevent HO progression.

Single cell sequencing reveals tendon cell subpopulations and altered gene expression pattern 

Therefore, Prof. Ouyang and his colleagues focused on searching for drugs that can inhibit angiogenesis process. They found that local injection of BIBF1120 significantly inhibited the neovascularization of tendon after injury, thus alleviating the tendon heterotopic ossification.

Small molecule inhibitor BIFB1120 significantly improved the microenvironment of tendon injury and inhibited heterotopic ossification