[ad_1]
An unfortunate “feed-forward” biological loop causes cartilage cells in an arthritic joint to actually contribute to the progression of the disease, say researchers at Duke University and Washington University in St. Louis.
Wolfgang Liedtke, pain researcher and mechanobiologist, professor of neurology at Duke, teamed up with Farshid Guilak, Duke’s former colleague and cartilage expert, now at Washington University School of Medicine, to examine the activity of sensitive ion channels to the pressure in the cartilage. Their study appears the week of March 22 in the Proceedings of the National Academy of Sciences.
Cartilage is a highly lubricated, low-friction elastic tissue that lines joint surfaces, cushions movement, and absorbs millions of cycles of mechanical compression. As the cartilage breaks down in painful osteoarthritis, the ends of the bones can come together bone to bone, increasing the 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 joint, piezoelectric channels send signals into the cell that can alter the activity of the gene in that cell.
Normally, chondrocytes produce an extracellular matrix, structural proteins and other biomolecules that give cartilage its mechanical rigidity, elasticity and low friction. But in osteoarthritis, the degeneration and dysfunction of these cells – which are unable to repair themselves through cell division – contribute to the gradual breakdown of cartilage.
Another hallmark of osteoarthritis is chronic low-grade inflammation caused by a signaling molecule called interleukin-1 alpha. Using cartilage cells from pigs and human joints collected for replacement surgeries, the researchers wanted to see how inflammation affects chondrocytes.
They found that interleukin signaling tells the cell to make more piezoelectric channels, which makes it even more sensitive to pressure and results in what the researchers call a harmful “ feed-forward ” loop that leads to a greater degradation of cartilage.
“Interleukin reprograms chondrocytes so that they are more susceptible to mechanical trauma,” Liedtke said. “The advance cycle grinds them slowly and the cell cannot be replaced.”
Liedtke describes a healthy chondrocyte as a bouncing sphere, “like a tennis ball” which is held rigid by its internal matrix of actin fibers. But as these cells lose their ability to replace actin fibers, “they get softer, softer.”
Unfortunately, researchers have found that the more spongy they become, the more piezo channels are created.
“The overexpressed piezo channels make the inflamed chondrocyte hypersensitive to mechanical microtrauma, thus increasing the risk of mechanically induced chondrocyte injury and subsequent progression of osteoarthritis,” said Biomedical Engineer Whasil Lee, lead author and co-correspondent who left the Liedtke-Lab to open his own laboratory at the University of Rochester
“It’s the cartilage reprogramming itself to do more damage,” Liedtke said.
For further confirmation, the researchers found that by blocking the activity of the piezo channels, the squishiness of the chondrocytes could be reversed.
Osteoarthritis is the most common form of arthritis and affects millions of people around the world with joint pain and stiffness. It is most commonly found in the knees, hips, and spine.
“We knew that the mechanical load on the joint is essential for maintaining the health of the cartilage,” said Guilak. In this study, we discovered a mechanism by which excessive load in inflammatory conditions can create a situation that can lead to progressive degeneration of the cartilage. “
“We’re always looking for feedback mechanisms as chronic disease facilitators,” Liedtke said. “Here we have found one, which opens the door for us to disease-modifying treatments, currently non-existent for osteoarthritis.”
Source link
