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Researchers in the United States and Japan have discovered a new mechanism that links age-related cartilage tissue stiffening with the repression of a key protein associated with longevity. These findings enhance the understanding of mechanisms that lead to the deterioration of joints that causes osteoarthritis, according to the authors of a new study, published Jan. 10 in Nature Communications.
In the study, researchers showed that increased stiffening of the extracellular matrix — a network of proteins and other molecules that surround and support tissues in the body — led to a decrease in a so-called longevity protein called Klotho (α-Klotho) in knee cartilage, brought about by epigenetic changes, or how DNA is organized and regulated. This Klotho decrease then damaged cells in healthy cartilage called chondrocytes. Conversely, exposing aged chondrocytes to a softer extracellular matrix restored the knee cartilage to a more youthful state.
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“This research enhances our mechanistic understanding of why osteoarthritis happens in the first place, and it paves the way for the development of therapeutics to prevent these changes. Such therapeutics are important because there are currently no disease-modifying treatments for osteoarthritis; the best we can do for now is minimize pain and disability,” said Fabrisia Ambrosio, 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. “Since matrix stiffening is a feature of aged tissues throughout the body, we anticipate that these findings may also have implications beyond cartilage repair for the field of aging research.”
As stiffening of extracellular matrix is a defining feature of cartilage aging, these findings demonstrate the role Klotho plays in the formation of osteoarthritis and offers new potential treatment targets to restore cartilage health. The researchers also note that their results may be applicable to the toll that epigenetic factors caused by aging takes on other tissues throughout the body.
Examining the root cause of irreversible cartilage damage
Osteoarthritis occurs when cartilage in a joint stiffens and begins to break down, which then damages the underlying bone, resulting in pain, swelling, and feelings of stiffness. Osteoarthritis is the most common form of arthritis, affecting approximately 32.5 million individuals in the United States alone, with numbers expected to rise with the aging population and trends in obesity. Osteoarthritis can significantly interfere with a person’s ability to perform routine daily tasks; about half of adults with the condition are of working age, which affects their ability to earn a living.
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There are currently no treatments to reverse this cartilage stiffening and the resulting damage. Treatments such as exercise, weight loss, physical therapy, medications, injections, and joint replacement surgery are aimed at reducing pain and improving mobility. Much has remained unknown about the molecular causes of this damage and how to treat it. These unknowns are especially germane to knee osteoarthritis, where no single event causes the cartilage damage, and the greatest predictive risk factor is aging.
Increasingly, researchers have sought to better understand the role how epigenetics can impact tissues and disease processes throughout the body.
Using advanced mass spectrometry technology, the researchers mapped out the trajectory of structural and protein changes in mice with knee osteoarthritis over the course of their lifetimes and according to sex. They then compared their findings to the current understanding of knee osteoarthritis in humans.
The researchers found that Klotho was heavily involved in the molecular process that led to osteoarthritis. This work was an extension of previous studies showing that Klotho protects mitochondria within skeletal muscle and plays a key role in skeletal muscle regeneration following injury. As people age, their Klotho levels go down, the reason it’s referred to as a longevity protein.
The new analysis revealed that when knee cartilage tissue became stiffer, the gene that codes for Klotho was repressed. They verified this in models of young and old chondrocyte cells responsible for cartilage formation, which were seeded in environments designed to mimic young and old tissue stiffness. Young chondrocyte cells looked old when put on a stiff surface due to the loss of Klotho, but when the researchers protected the cells from the stiffness in their environment, they observed chondrocyte health.
“These results provide a compelling new paradigm that will be important for the field in terms of understanding the connection between age-related tissue stiffening and risk for osteoarthritis with aging,” said Hirotaka Iijima, assistant professor at the Institute for Advanced Research and Graduate School of Medicine in Nagoya University.
Interestingly, the analysis also revealed that incidence of osteoarthritis increased in male mice with age, while female mice showed no onset of the disease, and their cartilage tissue was generally preserved. This unexpected finding differs from the response observed in people, where post-menopausal women are significantly more likely than men to develop severe knee osteoarthritis. These findings warrant further study, according to the authors, and a project is underway in Ambrosio’s lab to examine the effects menopause has on knee osteoarthritis at the molecular level.
Future research aims to address therapeutic gaps
With the latest findings, the researchers plan to study whether there are ways to intervene with the disease process that leads to osteoarthritis, such as by blocking the pathway that represses Klotho, even in the face of a stiff extracellular matrix environment. They hope their findings can be used to develop treatments for osteoarthritis and other conditions caused by aging.
“We’re interested in evaluating whether epigenetic regulation of Klotho and other longevity factors by the extracellular matrix may help explain functional decline of tissues throughout the system,” Ambrosio said.
Authorship, funding, disclosures
For additional authors, please see the list of authors here.
This study was supported in part by a grant-in-aid from the Japan Society for the Promotion of Science for Overseas Research Fellowships; research grants from the Uehara Memorial Foundation; National Institute on Aging grants R01AG052978, R01AG061005, and P2CHD086843; the National Institute of General Medical Sciences of the NIH under award number T32GM008208; JSPS KAKENHI grant number JP21H03302; Kyoto University Nano Technology Hub in Nanotechnology Platform Project, sponsored by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan; and the John and Posy Krehbiel Professorship in Orthopedics at the Mayo Clinic.
