Biological feed-forward loop drives cartilage cells in an arthritic joint to add to progression of the illness


Mar 23 2021 A regrettable biological “feed-forward” loop drives cartilage cells in an arthritic joint to in fact add to development of the disease, say researchers at Duke University and Washington University in Saint Louis.

Discomfort scientist and mechanobiologist Wolfgang Liedtke, a professor of neurology at Duke, partnered with former Duke coworker and cartilage professional Farshid Guilak, now at the Washington University School of Medicine, to take a look at the activity of pressure-sensitive ion channels in cartilage. Their research study appears the week of March 22 in the Proceedings of the National Academy of Sciences.

Cartilage is the extremely lubricated, low-friction, flexible tissue that lines joint surface areas, cushioning movements and absorbing millions of cycles of mechanical compression. As cartilage breaks down in agonizing osteoarthritis, completions of bones can come together bone-on-bone, increasing pain much more.

The cells that construct and keep cartilage are called chondrocytes, and on their surface can be discovered ion channels that are sensitive to force, called Piezo1 and Piezo2. In action to mechanical loads on the joint, Piezo channels send signals into the cell that can change gene activity because cell.

Usually, chondrocytes produce extracellular matrix, the structural proteins and other biomolecules that give cartilage its mechanical tightness, elasticity and low friction. However in osteoarthritis, degeneration and malfunction of these cells – which are incapable of repair work by cell division– add to the progressive breakdown of cartilage.

One of the other trademarks of osteoarthritis is persistent, low-grade inflammation, driven by a signaling molecule called interleukin-1 alpha. Using cartilage cells from pigs and from human joints removed for replacement surgeries, the scientists wished to see how inflammation impacts chondrocytes.

They discovered that interleukin signaling informs the cell to produce more Piezo channels, making the cell even more sensitive to pressure and resulting in what the scientists call a damaging ‘feed-forward’ loop that results in more breakdown of the cartilage.

“Interleukin reprograms the chondrocytes so that they’re more conscious mechanical trauma,” Liedtke stated. “The feed-forward cycle slowly grinds them down and the cell can not be replaced.”

Liedtke explains a healthy chondrocyte as a bouncy sphere, “like a tennis ball” which is kept stiff by its internal matrix of actin fibers. However as these cells lose their capability to replace actin fibers, “they get softer, more squishy.”

Regrettably, the researchers discovered that the more squishy they end up being, the more Piezo channels are produced.

“Overexpressed Piezo channels render the swollen chondrocyte hypersensitive to mechanical microtrauma, thus increasing the risk of mechanically-induced chondrocyte injury and subsequent development of osteoarthritis” said biomedical engineer, Whasil Lee, very first and co-corresponding author who moved from the Liedtke-Lab to open her own lab at the University of Rochester

“It’s cartilage reprogramming itself to do more damage,” Liedtke said.

For more confirmation, the researchers found that by obstructing the activity of the Piezo channels, the squishiness of chondrocytes might be reverted.

Osteoarthritis is the most typical type of arthritis and affects countless people worldwide with joint pain and stiffness. It is most typically found in the knees, hips and spinal column.

“We have understood that mechanical loading of the joint is vital for maintaining cartilage health, Guilak stated. “In this research study, we have actually discovered a system by which extreme loading under inflammatory conditions can develop a scenario that can cause progressive cartilage degeneration.”

“We’re constantly trying to find feed-forward mechanisms as facilitators of chronic illness,” Liedtke said. “Here we discovered one, which opens the door for us to come up with disease-modifying treatments, currently non-existent for osteoarthritis.”