Could this drug combo reverse arthritis?

Scientists have discovered that the use of two experimental osteoarthritis drugs in combination significantly reduces arthritis in rats.

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New research in rats brings hope for potential new arthritis treatment in humans.

The team at the Salk Institute for Biological Studies in La Jolla, CA, has also found that the drugs work on isolated human cartilage cells.

The results of this latest research now appear in the journal Protein & Cell.

According to the Centres for Disease Control and Prevention (CDC), osteoarthritis, or ‘wear and tear’ arthritis, typically occurs in a person’s hands, hips or knees.

Osteoarthritis causes the cartilage between bones to break down and the bones themselves to change shape, resulting in pain, stiffness, and swelling in and around the joints.

Osteoarthritis affects over 30 million adults in the United States. According to an article in the journal Bone Research, it is the main cause of disability in the U.S. because of the pain people associate with the disease.

There is currently no cure for osteoarthritis, so doctors usually treat the symptoms through pain medication, increasing physical activity, weight loss, supportive devices such as crutches, and, if necessary, surgery.

The scientists at the Salk Institute noted that the body’s ability to combat the degeneration of wear and tear damage on the joints decreases with age and that the joints of very young mammals often have far better regenerative properties.

This led them to speculate whether treatment could be developed that encouraged these regenerative properties in the joints of older mammals.

Previous research has suggested the molecules alpha-KLOTHO (aKLOTHO) and TGF beta receptor 2 (TGFβR2) as possible drugs in the treatment of osteoarthritis.

aKLOTHO affects the molecules that surround cartilage cells, helping to stop this supportive mesh from degrading, whereas TGFβR2 directly targets cartilage cells, stopping them from breaking down and encouraging them to produce more cells.

Each drug has had some success at stopping osteoarthritis in animal models. However, the results were modest. The Salk Institute team wondered whether the combination of these two drugs would have better results.

“We thought that by mixing these two molecules that work in different ways, maybe we could make something better,” says Paloma Martinez-Redondo, a Salk postdoctoral fellow and co-first author of the new study.

An effective arthritis treatment

Through the use of a harmless virus, the researchers gave the rats with osteoarthritis the DNA instructions for making the two types of molecules, while another group of rats received control particles.

After 6 weeks, the rats who received the control particles had more severe osteoarthritis in their knees. The disease had, in effect, moved from stage 2 to stage 4 osteoarthritis.

In comparison, the rats with the combination of aKLOTHO and TGFβR2 had significantly less arthritis.

They had thicker, healthier cartilage, fewer cartilage cells were dying, and there were more cartilage cells that were actively proliferating. For these rats, their arthritis reduced from stage 2 to stage 1.

“From the very first time we tested this drug combination on just a few animals, we saw a huge improvement,” says Isabel Guillen-Guillen, the paper’s co-first author. “We kept checking more animals and seeing the same encouraging results.”

On closer inspection, the scientists found that the drug combination affected genes related to inflammation and immune responses, giving them information to help understand precisely how the treatment was working, and what future areas to investigate.

Human arthritis

While the team conducted these initial investigations on rats, it also did experiments on isolated human cartilage cells to see if the results might be replicable in humans.

After treating the cells with the drug combination, the researchers found that the number of molecules they could associate with making the cartilage healthier increased.

“That’s not the same as showing how these drugs affect the knee joint in humans, but we think it’s a good sign that this could potentially work for patients,” says Martinez-Redondo.

There are two ways the team intends to develop the research. First, they plan to investigate whether the drugs can be administered in a soluble form rather than through a viral host.

Secondly, the team wants to see if the drug combo could be effective at preventing osteoarthritis before symptoms occur.

If so, this could open the door to a potentially far more effective treatment option for humans.

“We think that this could be a viable treatment for osteoarthritis in humans.”

– Pedro Guillen, co-corresponding author


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