Osteoarthritis is the most common form of arthritis, affecting over 250 million people worldwide. The condition brings joint pain and stiffness, gets worse over time, and cannot be cured. It’s a complex condition with a plethora of contributing factors that are still poorly understood.
In a bid to better understand the biological processes and perhaps reveal new treatment options, researchers from the University of Twente in the Netherlands have examined the microenvironment around cells in the joints.
They found that changes in the concentration of water-soluble material outside of cells, long thought to be just a harmless consequence of the condition, is in fact a fundamental driving force behind disease progression.
“This is a potential paradigm shift in our understanding of osteoarthritis,” said Kannan Govindaraj, lead author of the study published in Advanced Science. “It opens new avenues for researchers working on the condition’s pathology, regenerative therapy, and drug discovery.”
A concentration problem
As osteoarthritis advances, cartilage tissue — the white tensile tissue covering joints — is damaged, leading to more bone-to-bone contact and a grinding pain. Cartilage is primarily composed of a network of connective scaffolding called the extracellular matrix and cells called chondrocytes.
Changes in water-soluble molecules outside of the chondrocytes controls the water content and thus concentration of proteins and other biomolecules within the cells. In osteoarthritis, this dilutes the molecules inside chondrocytes and alters their molecular activity, making them more sensitive to inflammation and less responsive to signals that support joint health.
“Our study delves into the role of osmolarity in osteoarthritis progression,” said Marieke Meteling, one of the co-authors of the study. Osmolarity is a measure of how concentrated a solution is. In this case, its about the fluid in the joint surrounding the cells. “We explored a cellular mechanism, intracellular molecular crowding, that has never before been investigated in relation to joint diseases.”
The team found that changes in concentration of molecules in the cellular microenvironment, a phenomenon referred to as osmolarity, cause a disruption to healthy cellular behavior. Like changing the number of people in a crowded room influences how people interact with each other, adjusting the concentration of biomolecules within cells alters how proteins interact, and genes are expressed.
“Our study suggests that lower joint osmolarity may cause chondrocytes to increase their volume, diluting the concentrations of all biomolecules, such as proteins, inside the cells, which significantly impacts cellular function,” said Govindaraj.
The resulting molecular disruptions may cause the changes in sensitivity and responsiveness of chondrocytes. “Intracellular molecular crowding is a phenomenon previously associated with diseases like cancer, diabetes, and Alzheimer’s,” said Govindaraj. “While the decrease in osmolarity during osteoarthritis progression is well-documented, its role in disease pathology has never been explored before.”
Revealing that role could open up new avenues to researchers hunting for treatments, providing a new mechanism to target with interventions.
Clearing a path
The next challenge for the team, says Govindaraj, will be identifying ways to intervene in those pathways to restore normal function — something they have already made progress on.
“When we cultured chondrocytes from damaged joint tissue in a higher osmotic medium simulating physiological conditions, we observed a reversal of many impaired cellular functions towards a healthier state,” says Govindaraj.
Replicating laboratory results in humans is rarely straightforward, so there are many more steps between this revelation and its application in patients, but there is the potential that it may one day ease or even prevent the pain of millions of people.
“Although this breakthrough does not provide immediate relief for osteoarthritis patients,” he said, “it offers a crucial cellular mechanism for scientists to consider. Future investigations may focus on strategies to restore physiological intracellular molecular crowding in damaged joints, paving the way for successful treatment strategies and offering hope for those suffering from this debilitating condition.”
Reference: Jeroen Leijten, et al., Osmolarity-Induced Altered Intracellular Molecular Crowding Drives Osteoarthritis Pathology, Advanced Science (2024). DOI: 10.1002/advs.202306722
Feature image credit: Towfiqu barbhuiya on Unsplash
