Scientists have engineered cartilage cells to produce an anti-inflammatory drug when under stress.
The drug blocked the destructive effects of inflammation, highlighting the potential of the approach. In the future, cartilage and replacement tissues could be "designed" to defend themselves from rejection.
Why "program" the cartilage to heal itself
Joints such as those in the knees and hands rely on cartilage tissue to keep the bones from rubbing together. Wear and tear over a lifetime can cause cartilage to break down, resulting in a painful condition called osteoarthritis.
Symptoms of osteoarthritis can include joint pain, stiffness and swelling. Hundreds of millions of adults around the world live with this condition. Currently, there are no treatments to prevent or reverse its progression.
The researchers were interested in growing new cartilage in the laboratory so that it could be implanted in joints. However, arthritis joints contain many molecules that promote chronic inflammation. This inflammation, in addition to the physical stress produced by normal movement, it can also quickly destroy replacement cartilage.
The research
A research group led by Dr. Farshid Guilak from Washington University in St. Louis tested whether cartilage cells could be engineered to protect themselves from inflammation. In a proof-of-concept study, the team altered cartilage cells from pigs to produce an anti-inflammatory molecule when you are stressed.
The results were published in Science Advances.
The researchers first identified a protein called TRPV4 in the membrane of cartilage cells which detects changes within the cells under compression. They found that TRPV4 is activated by a change in the fluid in cells called osmotic load. The protein can also be triggered by mechanical forces.
The reaction is remarkable
The team demonstrated that, in response to stress, TRPV4 activates specific genetic pathways in cartilage cells associated with inflammation and metabolism.
Researchers have modified these genetic circuits to produce an anti-inflammatory molecule called interleukin-1 receptor antagonist (IL-1Ra). Cells with these loops were then grown to form cartilage.
Self-healing cartilage
When exposed to mechanical forces or osmotic load, the cells are engineered produced IL-1Ra. The timing and duration of production depended on the genetic circuit used.
This suggests that manufacturing could be customized by leveraging different cellular pathways that turn on and off at different times. Cartilage that thanks to bioengineering produces “cures” at different times, and in response to different types of stimuli.
Finally, the researchers tested whether IL-1Ra production could protect cartilage cells in an inflammatory environment. An environment similar to that observed in osteoarthritis.
They therefore exposed the engineered cartilage to both an inflammatory molecule and an osmotic load for three days.
Whoever does it alone makes for three
By the end of that time, the cartilage that was not producing IL-1Ra was breaking down. Conversely, the cartilage that produced the molecule retained its structure and strength.
These findings demonstrate the ability to engineer living tissues to produce your own therapeutic drugs. “We believe this strategy could allow us to program cells to deliver therapies in response to a variety of medical problems,” Guilak says.
