A new study from scientists at The Scripps Research Institute finds that FoxO proteins control our risk of developing osteoarthritis as we age. The work was published yesterday in Science Translational Medicine.
"We discovered that FoxO transcription factors control the expression of genes that are essential for maintaining joint health," says Martin Lotz, M.D., senior author of the study. "Drugs that boost the expression and activity of FoxO could be a strategy for preventing and treating osteoarthritis."
Previous research from Lotz' lab showed that with age, levels of FoxO proteins decreased in cartilage. In addition, the expression of genes required for autophagy was lower in people with osteoarthritis.
In this new study, the researchers found that in FoxO deficient mice, cartilage degenerated at a younger age compared to a control mouse. The FoxO knockout mice also had more severe forms of post-traumatic osteoarthritis and were more vulnerable to cartilage damage when treadmill running.
It turns out that FoxO proteins helped with the production of lubricin protein, which protects cartilage from friction and wear. The lack of lubricin was associated with a loss of healthy cells in the superficial zone of the knee joint. Without FoxO proteins, there was an increase in inflammation-related genes and low levels of autophagy-related genes.
"The housekeeping mechanisms, which keeps cells healthy, were not working in these knockout mice," Lotz explains.
To see if therapeutically targeting FoxO would help, the researchers used genetic approaches to increase FoxO expression and found that the levels of lubricin and protective genes returned to normal.
The next steps in this project are to develop molecules that can enhance FoxO and test them in osteoarthritis experimental models.
Image: Knee joints from control and FoxO deficient mice. The areas in red are joint cartilage which is destroyed in FoxO deficient mice after treadmill running. Image courtesy of Lotz Lab at The Scripps Research Institute.