An unfortunate biological “feed-forward” loop drives cartilage cells in arthritic joints to contribute to the progression of the disease, say researchers at Duke University and Washington University in Saint Louis.
Pain researcher and mechanicist Wolfgang Liedtke, professor of neurology at Duke, in partnership with former Duke colleague and cartilage expert Farshid Guilak, now at the University of Washington School of Medicine, to study activity pressure-sensitive ion channels in cartilage. Their study will appear the week of March 22 in the Proceedings of the National Academy of Sciences.
Cartilage is the full-fat, low-freezing mud material that stretches a joint surface, cubic movements and contains millions of cycles of mechanical compression. As cartilage breaks down in chronic osteoarthritis, the ends of the bones can come together bone-by-bone, increasing pain even more.
The cells that build and maintain cartilage are called chondrocytes, and on their surface are force-sensitive ion channels, called Piezo1 and Piezo2. In response to mechanical loads on the component, Piezo channels send signals to the cell that may alter gene activity in that cell.
Chondrocytes usually produce an extracellular matrix, the structural proteins and other biomolecules that give cartilage its mechanical stiffness, elasticity and low friction. But in osteoarthritis, the shrinkage and degeneration of these cells – which cannot be repaired by cell division – contributes to progressive cartilage rupture.
One of the other symptoms of osteoarthritis is low-grade, molecular-directed inflammation called interleukin-1 alpha. Using cartilage cells from pigs and removed human joints for new surgeries, the researchers wanted to see how inflammation affects chondrocytes.
They found that interleukin signals tell the cell to produce more Piezo channels, making the cell even more sensitive to pressure and leading to what the researchers call a harmful loop ‘feed’. -forward ‘which leads to further breakdown of the cartilage.
“Interleukin reprints into chondrocytes so that they become more sensitive to mechanical trauma,” Liedtke said. “The feed-forward cycle erodes slowly and the cell cannot be replaced.”
Liedtke describes a healthy chondrocyte as a bouncy field, “like a tennis ball” held indefinitely by the inner matrix of actin wood. But as these cells lose the ability to replace actin fibers, “they become softer, more squishy.”
Unfortunately, the researchers found that the more squishy they are, the more Piezo channels are created.
“Piezo’s Overexpressed Channels expose the hypersensitive inflamed chondrocyte to mechanical microtrauma, thereby increasing the risk of mechanically induced chondrocyte injury and subsequent progression of osteoarthritis” said biomedical engineer Whasil Lee, the first author and correspondent to move from the Liedtke-Lab to open its own laboratory at the University of Rochester
“Cartilage reprogramming is itself to do more damage,” Liedtke said.
For further confirmation, the researchers found that, by inhibiting the activity of the Piezo channels, squishiness could reverse chondrocytes.
Osteoarthritis is the most common form of arthritis and affects millions of people worldwide with joint pain and stiffness. It is most commonly found in the knees, buttocks and spine.
“We know that mechanical loading of the joint is essential for maintaining cartilage health, Guilak said.” In this study, we have found a mechanism by which overloading under blowing conditions can create a could lead to progressive cartilage degeneration. “
“We’re always looking for nutritional supplements as enablers of infectious disease,” Liedtke said. “Here we found one, which opens the door for us to come up with disease-modifying treatments, that are not currently available for osteoarthritis.”