Researchers at Washington University School of Medicine in St. Louis found that gene therapy in mice helped build strength and significant muscle mass quickly, while reducing the severity of osteoarthritis. The gene therapy also prevented obesity, even when the mice were fed a high-fat diet. [Mike Worful]

Researchers at Washington University and Shriners Hospitals for Children have developed a gene therapy that in initial in vivo tests reduced the severity of osteoarthritis (OA) in mice, helped treated animals to build significant muscle mass, and also prevented them from putting on weight, even when fed a high-fat diet (HFD). Animals given the adeno-associated virus (AAV)-based vector encoding the gene for follistatin were also less sensitive to osteoarthritis-related pain, and demonstrated cardiovascular benefits. The team suggested that their gene therapy approach may lead to the development of new treatment strategies for OA, but also potentially for obesity and associated metabolic conditions, and muscle-wasting disorders.

“Obesity is the most common risk factor for osteoarthritis,” said senior investigator Farshid Guilak, PhD, the Mildred B. Simon research professor of orthopedic surgery and director of research at Shriners Hospitals for Children, St. Louis. “Being overweight can hinder a person’s ability to exercise and benefit fully from physical therapy. We’ve identified here a way to use gene therapy to build muscle quickly. It had a profound effect in the mice and kept their weight in check, suggesting a similar approach may be effective against arthritis, particularly in cases of morbid obesity.”

The researchers reported on their studies in Science Advances, in a paper titled, “Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat diet-induced obesity.”

Osteoarthritis is characterized by cartilage degeneration, joint inflammation, and bone remodeling, the authors explained. There are currently no disease-modifying treatments available for the disorder, but obesity is a known key risk factor. “Previous studies demonstrate that obesity and dietary fatty acids (FAs) play a critical role in the development of OA, and metabolic dysfunction secondary to obesity is likely to be a primary risk factor for OA.”

Exercise and physical therapy are often recommended to help people who have arthritis, alongside weight loss, if relevant. Exercise and physical therapy can strengthen muscle—a benefit that also can reduce joint pain. But it can take months to build muscle mass and strength, and exercising may be difficult for patients who are suffering from osteoarthritis-related joint pain, and particularly for older people who are overweight. “Thus, targeted pharmacologic or genetic inhibition of muscle-regulatory molecules such as myostatin provides a promising approach to improving muscle metabolic health by increasing glucose tolerance and enhancing muscle mass in rodents and humans.”

One potential approach might center on follistatin (FST), a protein that binds to myostatin, which is involved in modulating skeletal muscle mass and acts to keep muscle growth in check. “FST, a protein that binds myostatin and activin, may have the potential to enhance muscle formation while inhibiting inflammation,” the team suggested. “In the context of OA, we hypothesize that FST delivery using a gene therapy approach has multifactorial therapeutic potential through its influence on muscle growth via inhibition of myostatin activity.” The team reasoned that using gene therapy to trigger overexpression of FST in obese mice could feasibly increase muscle mass, mitigate obesity-associated metabolic inflammation, and hold back OA.

To investigate this further, the researchers, including first author Ruhang Tang, PhD, a senior scientist in Guilak’s laboratory, administered a single dose of an AAV vector carrying the gene for FST to eight-week-old mice that were fed a normal diet, and in animals that were fed a high-fat diet.

The results showed that muscle mass more than doubled in animals that received the gene therapy at eight weeks old, and their strength nearly doubled, too, without additional exercise, and even when they continued to eat a high-fat diet. The mice also had less cartilage damage related to injury-induced osteoarthritis, lower numbers of inflammatory cells and proteins in their joints, fewer metabolic problems, and healthier hearts and blood vessels than littermates that did not receive the gene therapy. The treatment in addition staved off obesity, even when the mice ate an extremely high-fat diet, and treated animals were significantly less sensitive to pain. “Our results show that FST delivery mitigated pain sensitivity in OA joints, a critical aspect of clinical OA,” the authors wrote.

“Our findings demonstrate that a single injection of AAV-mediated FST gene therapy ameliorated systemic metabolic dysfunction and mitigated OA-associated cartilage degeneration, synovial inflammation, and bone remodeling occurring with joint injury and an HFD,” they stated. “FST gene therapy showed a myriad of notable beneficial effects on joint degeneration following joint injury while mitigating HFD-induced obesity.”

One potential concern was that muscle growth prompted by the gene therapy might also lead to cardiac hypertrophy, in which the heart’s walls thicken. But the results conversely showed that heart function in the treated mice improved, as did cardiovascular health in general. “In addition to these effects of skeletal muscle, we found that FST gene therapy normalized many of the deleterious changes of an HFD on cardiac function without causing hypertrophy,” the investigators further noted.

While longer-term studies will be needed to determine the safety of this type of gene therapy, the strategy could be particularly beneficial for patients with conditions such as muscular dystrophy that make it difficult to build new muscle. “As AAV gene therapy shows an excellent safety profile and is currently in clinical trials for a number of conditions, such an approach may allow the development of therapeutic strategies not only for OA but also, more broadly, for obesity and associated metabolic conditions, including diseases of muscle wasting,” the scientists concluded.

In the meantime, Guilak, who also co-directs the Washington University Center for Regenerative Medicine and is a professor of biomedical engineering and of developmental biology, said more traditional methods of muscle strengthening, such as lifting weights or physical therapy, remain the first line of treatment for patients with osteoarthritis.

“Something like this could take years to develop, but we’re excited about its prospects for reducing joint damage related to osteoarthritis, as well as possibly being useful in extreme cases of obesity,” he said.

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