Biological feedforward loops drive chondrocytes in arthritic joints to contribute to disease progression

March 23, 2021

According to researchers at Duke University and the University of Washington in St. Louis, the unfortunate biological “feedforward” loop drives the chondrocytes in the arthritic joints and actually contributes to the progression of the disease.

Wolfgang Liedtke, a pain researcher and mechanical biologist, is a professor of neurology at Duke University, a former Duke University colleague, and a cartilage sensation in collaboration with the cartilage expert Farshid Guilak, now at Washington University School of Medicine. The activity of the pressure ion channel was investigated.Their study was in the week of March 22 Minutes of the National Academy of Sciences..

Cartilage is a highly lubricated, low-friction elastic tissue that lines the joint surface, relaxes movement, and absorbs millions of cycles of mechanical compression. When cartilage is destroyed in painful osteoarthritis, the ends of the bones connect the bones together, which can further increase the pain.

The cells that build and maintain cartilage are called chondrocytes, and on their surface are ion channels called piezo 1 and piezo 2, which are sensitive to force. In response to mechanical loads on joints, piezo channels can signal cells to alter their genetic activity.

Normally, chondrocytes produce extracellular matrix, structural proteins, and other biomolecules that give cartilage mechanical stiffness, elasticity, and low friction. However, in osteoarthritis, the degeneration and dysfunction of these cells, which cannot be repaired by cell division, contributes to the progressive destruction of cartilage.

One of the other features of osteoarthritis is chronic mild inflammation caused by a signaling molecule called interleukin-1 alpha. Researchers wanted to see how inflammation affects chondrocytes using chondrocytes in pigs and human joints that have been resected for replacement surgery.

They direct interleukin signaling to the cells to produce more piezo channels, making them more sensitive to pressure and leading to harmful “feed forward” loops that lead to more cartilage destruction. I found that.

“Interleukins reprogram chondrocytes to make them more sensitive to mechanical trauma,” Rietke said. “The feedforward cycle crushes them slowly and the cells cannot be replaced.”

Liedtke describes healthy chondrocytes as “tennis ball-like” elastic spheres that are held tight by the internal matrix of actin fibers. However, when these cells lose the ability to replace actin fibers, “they become softer and more squeezed.”

Unfortunately, researchers have found that the more squeeze, the more piezo channels are created.

“Overexpressed piezochannels make inflamed chondrocytes hypersensitive to mechanical microtrauma, increasing the risk of mechanically induced chondrocyte damage and subsequent progression of osteoarthritis.” , Liedtke-Lab opens his own lab at the University of Rochester

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

For further confirmation, researchers have found that blocking the activity of piezo channels can restore chondrocyte squeeze.

Osteoarthritis is the most common form of arthritis, affecting millions of people around the world with joint pain and stiffness. Most commonly found on the knees, hips and spine.

“We know that mechanical loading of joints is essential for maintaining cartilage health. In this study, excessive loading under inflammatory conditions can lead to progressive cartilage degeneration. Clarified the mechanism that creates a certain situation. “

“We are always looking for a feedforward mechanism as a promoter of chronic disease,” Liedtke said. “Here we have found something that opens the door to devising disease-modifying therapies that do not currently exist in osteoarthritis.”