Scientists discover new clues about joint disease and possible treatments

A new study has uncovered important clues about why joints get weaker with age and obesity鈥攁nd it may help lead to better treatments for osteoarthritis (OA), a painful disease that affects millions of people worldwide.

Osteoarthritis is a common condition where the protective cushioning between your bones 鈥� called cartilage 鈥� gradually wears down over time. This causes pain, stiffness, and trouble moving. Osteoarthritis is the most common form of arthritis, affecting 32.5 million U.S. adults. Aging and obesity are the two biggest risk factors for OA. So far, there are no drugs that can stop or reverse the disease. Researchers have identified a protein, SIRT5, that may offer a new direction for developing treatments.

SIRT5 is a type of protein found in cells that helps control metabolism. Scientists already knew that SIRT5 helps regulate other proteins by removing certain chemical tags called malonyl groups in a process called demalonylation. But they didn鈥檛 know how this affects cartilage cells or chondrocytes, which are crucial for joint health.

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The research team from 花季传媒's Heritage College of Osteopathic Medicine, the University of Utah and the Buck Institute for Research on Aging wanted to better understand the role chondrocyte metabolism plays in the development of osteoarthritis. They found that as people and animals age, levels of SIRT5 in cartilage go down, while levels of malonylation go up. This change appears to hurt the function of chondrocytes and could lead to cartilage damage.

The researchers, led by Shouan Zhu, Ph.D., Osteopathic Heritage Foundation Ralph S. Licklider, D.O., endowed professor and investigator with the Ohio Musculoskeletal and Neurological Institute and Diabetes Institute at the Heritage College, studied both human and mouse cartilage samples. They found that older cartilage had less SIRT5 and more malonylation. They also studied mice that were fed high-fat diets to mimic obesity. Mice that lacked SIRT5 and were also obese had worse joint damage than control mice.

However, the effects were different between male and female mice. Male mice without SIRT5 had more severe cartilage loss and joint pain when fed a high-fat diet. Female mice were somewhat protected, though they still showed some signs of damage.

This shows that SIRT5 plays a role in protecting joints from the harmful effects of aging and obesity, and that this protection might work differently in males and females.

To understand how SIRT5 helps cartilage cells, scientists looked at the proteins inside chondrocytes from mice with and without SIRT5. They discovered that without SIRT5, important proteins for building cartilage were reduced, while proteins linked to inflammation were increased.

They also found that malonylation disrupts a key part of energy production in cells called glycolysis. One important enzyme, GAPDH, worked much more slowly when malonylated. This suggests that losing SIRT5 leads to energy problems in cartilage cells, making it harder for them to stay healthy.

The researchers also found a rare genetic mutation in the SIRT5 gene in a family where many members had early and severe osteoarthritis. This mutation, called SIRT5F101L, makes SIRT5 less effective at removing malonyl groups.

When they tested this mutated version of SIRT5 in lab-grown cartilage cells, they found it led to more malonylation and less production of cartilage-building proteins鈥攋ust like what they saw in SIRT5-deficient mice.

This means the SIRT5F101L mutation might be a genetic cause of osteoarthritis in some families.

Featured on the cover and  published in , this study is one of the first to link the SIRT5-malonylation pathway directly to joint health. It suggests that boosting SIRT5 activity鈥攐r reducing malonylation鈥攃ould be a new way to treat or prevent osteoarthritis, especially in people who are aging or obese.

鈥淯nderstanding how metabolism affects cartilage is a big step forward,鈥� said Zhu. 鈥淭his gives us a new way to think about treatments鈥攏ot just for symptoms, but for the root causes of osteoarthritis.鈥�

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