‘Feed-forward’ Loop in Cartilage Cells Worsens Osteoarthritis
An unfortunate ‘feed-forward’ loop in cartilage cells appears to exacerbate arthritis, according to researchers Duke University and Washington University in Saint Louis.
Cartilage resists compressive forces, enhances bone resilience, and provides support on bony areas where there is a need for flexibility. In osteoarthritis, the most common form of arthritis, the cartilage breaks down, allowing painful bone-on-bone contact. Osteoarthritis is the and affects millions of people worldwide with joint pain and stiffness. It is most commonly found in the knees, hips and spine.
Chondrocytes build and maintain cartilage, with force-sensitive ion channels on their surface, which are called Piezo1 and Piezo2. Piezo channels respond to mechanical loads on the joint by sending signals into the cell that can change gene activity.
In osteoarthritis, degeneration and malfunction of chondrocytes, which are unable to repair themselves by division, contributes to the progressive breakdown of cartilage. Osteoarthritis is als marked by chronic, low-grade inflammation, driven by interleukin-1 alpha, a signalling molecule. Taking cartilage cells from pigs and from human joints removed for replacement surgeries, the researchers investigated the way inflammation affects chondrocytes.
The researchers found that interleukin signaling causes the chondrocytes to produce more Piezo channels, in turn increasing their sensitivity to pressure and resulting in what the researchers term a harmful ‘feed-forward’ loop that leads to further cartilage breakdown.
“Interleukin reprograms the chondrocytes so that they’re more sensitive to mechanical trauma,” Liedtke said. “The feed-forward cycle slowly grinds them down and the cell cannot be replaced.”
Liedtke likened healthy chondrocyte to “a tennis ball”, a bouncy sphere which is kept stiff by its internal matrix of actin fibres. But as these cells lose their ability to replace actin fibres, “they get softer, more squishy.”
However, more Piezo channels were created as the chondrocytes became squishier.
“Overexpressed Piezo channels render the inflamed chondrocyte hypersensitive to mechanical microtrauma, thus increasing the risk of mechanically-induced chondrocyte injury and subsequent progression of osteoarthritis,” said first and co-corresponding author and biomedical engineer, Whasil Lee, who moved from the Liedtke-Lab to open her own laboratory at the University of Rochester
“It’s cartilage reprogramming itself to do more damage,” Liedtke said.
To confirm this relationship, the researchers blocked the activity of the Piezo channels and observed that the ‘squishiness’ of chondrocytes was reverted.
“We have known that mechanical loading of the joint is essential for maintaining cartilage health,” Guilak said. “In this study, we have uncovered a mechanism by which excessive loading under inflammatory conditions can create a situation that can lead to progressive cartilage degeneration.”
“We’re always looking for feed-forward mechanisms as facilitators of chronic disease,” Liedtke said. “Here we found one, which opens the door for us to come up with disease-modifying treatments, currently non-existent for osteoarthritis.”
Source: Duke University
Journal information: “Inflammatory Signaling Sensitizes Piezo1 Mechanotransduction in Articular Chondrocytes as a Pathogenic Feed-Forward Mechanism in Osteoarthritis,” Whasil Lee, et al. PNAS, March 22, 2021, DOI: 10.1073/pnas.2001611118
