Novel mechanism behind osteoarthritis discovered holding new treatment potential

Researchers in the United States and Japan have discovered a new mechanism that links age-related cartilage tissue stiffening with the repression of a key protein associated with longevity. These findings enhance the understanding of mechanisms that lead to the deterioration of joints that causes osteoarthritis, according to the authors of a new study, published in Nature Communications.

In the study, researchers showed that increased stiffening of the extracellular matrix led to a decrease in a so-called “longevity protein” called Klotho (α-Klotho) in knee cartilage brought about by epigenetic changes. This Klotho decrease then damaged the cells in healthy cartilage called chondrocytes. Conversely, exposing aged chondrocytes to a softer extracellular matrix restored the knee cartilage to a more youthful state.

As stiffening of extracellular matrix is a defining feature of cartilage aging, these findings demonstrate the role Klotho plays in the formation of osteoarthritis and offers new potential treatment targets to restore cartilage health.

Using advanced mass spectrometry technology, the researchers mapped out the trajectory of structural and protein changes in mice with knee osteoarthritis over the course of their lifetimes and according to sex. They then compared their findings to the current understanding of knee osteoarthritis in humans.

The researchers found that Klotho was heavily involved in the molecular process that led to osteoarthritis.As people age, their klotho levels go down, hence why it’s referred to as a longevity protein. The new analysis revealed that when knee cartilage tissue became stiffer, the gene that codes for Klotho was repressed.

Reference:

Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity,Nature Communications,doi 10.1038/s41467-022-35359-2