New work from a multi-center (Nagoya University, in Japan and Harvard University in Boston) research is deepening our understanding of what leads to joint deterioration and osteoarthritis (OA).
The study, “Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity,” was published in Nature Communications on January 10, 2023.
Fabrisia Ambrosio, Ph.D., M.P.T., co-author of the study and inaugural director of the Discovery Center for Musculoskeletal Recovery at Spaulding Rehabilitation Hospital, and member of the faculty of physical medicine and rehabilitation at Harvard Medical School, explained the challenges of understanding the biologic processes underlying cartilage disease to OTW. “Hyaline cartilage is an avascular tissue with limited self-healing properties. As such, with injury or in the setting of disease, the resident cells in cartilage, chondrocytes, increase anabolic activity in an attempt to repair the damaged extracellular matrix. Despite this increased activity, chondrocytes fail to repair the extracellular matrix and, instead, cartilage tissue is generally replaced with the mechanically inferior fibrocartilage.”
In the new paper, the Nagoya and Harvard based research team outlined the structural and proteomic changes associated with knee OA in mice across the animal lifespan and according to sex. They were able to identify the longevity protein, α-Klotho, as a regulator of chondrocyte health (in both mice and human cartilage). The team then used in vitro engineered models to reveal that an age-related increase in matrix stiffness compromises chondrocyte integrity and reduces α-Klotho expression.
Interestingly, when the research team used drugs to reduce cartilage stiffness in older mice, levels of α-Klotho levels increased, and cartilage integrity was restored.
Ah, Yes, Menopause!
“As expected,” said Dr. Ambrosio, “we observed progressive cartilage degeneration as animals got older, just as is seen in humans. However, when we segregated our data by sex, we found that the changes observed were entirely driven by male mice. Female mice, on the other hand, displayed a minimal loss of cartilage integrity as they got older. This histological observation was consistent with proteomic changes, as evidenced by our data showing the progressive change in PI3K/Akt signaling in male, but not female, mice.”
“These findings were surprising considering that, in human populations, osteoarthritis tends to be much more severe in females than in males—exactly the opposite of what we observed.”
“What we didn’t appreciate at the time is that most aged female mice do not undergo menopause as do human female counterparts. Based on these data, we are now very interested to investigate 1) the role of menopause in osteoarthritis in females and 2) the role of menopause in contributing to extracellular matrix stiffening in females.”
“Not only does our work suggest that a stiff microenvironment contributes to a loss of Klotho expression, but previous studies have shown that a loss of Klotho also contributes to matrix stiffening. A vicious cycle therefore ensues. However, our work suggests that restoration of chondrocyte health may be possible.”
“Specifically, we found that aged chondrocytes seeded on a soft matrix displayed a more youthful phenotype. In a set of parallel animal studies, we similarly found that altering extracellular matrix biophysical properties resulted in enhanced cartilage integrity in aged mice.”
“Given these findings, we are now pursuing opportunities for the development of new therapeutics to counteract age-related declines in cartilage health.”
“Such opportunities may involve, for example, strategies to block the mechanical signals from the matrix to the cell that are responsible for inhibiting the gene expression of Klotho and/or strategies to inhibit the pathways that promote matrix stiffening in the first place.”
