Study Explores Role of Leptin in Development of Osteoarthritis

Obesity is considered to be one of the greatest risk factors for osteoarthritis, a progressive musculoskeletal disorder that is characterized by loss of joint cartilage.

Leptin is a protein hormone that is produced by fat cells and responsible for regulating appetite and metabolism. The amount of leptin in the body increases as body fat increases with obese people having high concentrations of the hormone circulating in their bodies.

A mouse study has now found a role for leptin as a metabolic link between obesity and altered cartilage metabolism in joints.

"We were completely surprised to find that mice that became extremely obese had no arthritis if their bodies didn't have leptin," said Farshid Guilak, study author. "Although there was some earlier evidence that leptin might be involved in the arthritis disease process, we didn't think that there would be no arthritis at all."

Leptin influences many of the factors involved in osteoarthritis, body weight, inflammation, sex hormone levels, and bone metabolism, said lead author Tim Griffin.

The role of obesity as a risk factor for osteoarthritis is well characterized, but it was thought to be merely a case of overloading joints with extra weight. "It hadn't been studied beyond that," Guilak said. "We knew from other studies that obese people got arthritis in their hands, too, which don't bear weight. This indicated that something besides just body-weight level affected their joints."

The researchers set out to learn whether the increased body fat of obesity causes an inflammatory response in joints, an imbalance of the immune system signaling proteins called cytokines and other chemicals in osteoarthritis.

They studied mice that were leptin-deficient or deficient in leptin receptors, mice that didn't have any effective leptin in their bodies. Both types of mice overate and gained weight. Then they compared the study mice with normal mice to document knee osteoarthritis. The measurements included pro- and anti-inflammatory cytokines present in arthritis, and several tests to assess bone changes in the knees of the mice.

The knee bones of the leptin-free, obese mice did change, but without forming osteoarthritis. The levels of inflammatory cytokines, which correlate with arthritis, were largely unchanged in these mice. The results suggested that leptin may have a dual role in the development of osteoarthritis by regulating both the skeletal and immune systems.

"Obesity is still the number one preventable risk factor of osteoarthritis, but now it seems body fat by itself is not what is causing it," Guilak said. "If you are obese, there are benefits to losing weight in terms of arthritis. For example, if you are obese and lose just 10 pounds, pain decreases significantly. Pain modulation is another clue it might be a chemical or systemic metabolic effect, rather than just a mechanical effect of less weight on the joints."

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References:
1. Timothy M. Griffin, Janet L. Huebner, Virginia B. Kraus, and Farshid Guilak. Extreme Obesity Due to Impaired Leptin Signaling in Mice Does Not Cause Knee Osteoarthritis. Arthritis & Rheumatism; DOI: 10.1002/art.24854.