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Engineered cartilage produces anti-inflammatory drug

From NIH Research Matters

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. This leads to a condition called osteoarthritis.

Chondrocyte squeezed into tip of micropipette
A cartilage cell, called a chondrocyte, is stimulated with a very small glass pipette, about 1/5 the diameter of a human hair. The cells were engineered to release a drug that combats inflammation when they undergo compression. Guilak lab, Washington University School of Medicine in St. Louis

The symptoms of osteoarthritis can include joint pain, stiffness, and swelling. More than 30 million adults nationwide are living with the condition. Currently, no treatments exist to prevent or reverse its progression.

Researchers have been interested in growing new cartilage in the lab that could be implanted into joints. However, joints with arthritis contain many molecules that promote chronic inflammation. This inflammation, plus the physical stress produced by normal movement, can destroy replacement cartilage quickly.

A research team led by Dr. Farshid Guilak from Washington University in St. Louis has been testing 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 stressed.

The study was funded in part by NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute on Aging (NIA), and National Center for Advancing Translational Sciences (NCATS). Results were published on January 27, 2021, in Science Advances.

The researchers first identified a protein called TRPV4 in the membrane of cartilage cells that senses alterations within cells under compression. They found that TRPV4 becomes activated by a change to the fluid in cells called osmotic loading. The protein can also be triggered by mechanical forces.

The team showed that, in response, TRPV4 activates specific genetic pathways in cartilage cells associated with inflammation and metabolism. The researchers modified these genetic circuits to produce an anti-inflammatory molecule called interleukin-1 receptor antagonist (IL-1Ra). Cells with these circuits were then grown to form cartilage.

When exposed to either mechanical forces or osmotic loading, the engineered cells produced IL-1Ra. The timing and duration of production depended on which genetic circuit was used. This suggests that production could be customized by harnessing different cellular pathways that turn on and off at different times.

Finally, the researchers tested whether production of IL-1Ra could protect cartilage cells in an inflammatory environment, similar to that seen in osteoarthritis. They exposed the engineered cartilage to both an inflammatory molecule and osmotic loading for three days.

By the end of that period, cartilage that didn’t produce IL-1Ra was breaking down. In contrast, cartilage that produced the molecule maintained its structure and strength.

These findings demonstrate the ability to engineer living tissue to produce its own therapeutic drugs. “We think this strategy could be a framework for doing what we might need to do to program cells to deliver therapies in response to a variety of medical problems,” Guilak says.

—by Sharon Reynolds

This research was funded in part by NIA grants AG46927, AG15768, and AG28716.

References: A synthetic mechanogenetic gene circuit for autonomous drug delivery in engineered tissues. Nims RJ, Pferdehirt L, Ho NB, Savadipour A, Lorentz J, Sohi S, Kassab J, Ross AK, O'Conor CJ, Liedtke WB, Zhang B, McNulty AL, Guilak F. Sci Adv. 2021 Jan 27;7(5):eabd9858. doi: 10.1126/sciadv.abd9858. Print 2021 Jan. PMID: 33571125.