Osteoarthritis is one of the most common ailments of an aging population, but there aren’t many treatment options besides taking pain killers or getting a full joint replacement. Now, researchers at the Salk Institute have found that a combination of two experimental drugs appears to reverse the symptoms of the disorder, with successful tests conducted in rats and in human cells in the lab.

As we age, our bodies gradually lose the ability to repair damage as fast as it needs to. That means that tissues subjected to high-intensity long-term use, such as cartilage in joints, are especially prone to wearing out. That manifests itself in the common condition of osteoarthritis, resulting in pain when that joint moves.

In the past, two molecules have been identified as having decent potential for treating the disease – alpha-KLOTHO (αKLOTHO) and TGF beta receptor 2 (TGFβR2). Previous tests only showed moderate success, so the researchers on the new study decided to see if they fared any better when used together.

Importantly, the molecules work in different ways. TGFβR2 acts directly on cartilage cells, improving their ability to proliferate, while αKLOTHO works on the extra-cellular matrix that surrounds cartilage cells, keeping it from degrading.

And sure enough, the combo worked much better than either drug did alone. In rats that had osteoarthritis but were otherwise healthy, the team administered viral particles that contained either the DNA instructions for making the two molecules, or placebo particles.

After six weeks, the team examined the cartilage in the rats’ knees. The control group didn’t do too well – in that time, the disease had progressed from stage 2 to stage 4. But in the test group, the disease hadn’t just slowed down, it had reversed from stage 2 back to stage 1. This meant the cartilage had gotten thicker, with fewer cells dying and more of them actively growing.

(Image 1) A healthy rat's knee joint. (Image 2) a joint with grade 2 osteoarthritis. (Image 3) a control group knee that has worsened to grade 4 osteoarthritis. (Image 4) a treated rat's knee joint, which has improved to grade 1 (mild) after receiving the drug combo Salk Institute

“From the very first time we tested this drug combination on just a few animals, we saw a huge improvement,” says Paloma Martinez-Redondo, first author of the study. “We kept checking more animals and seeing the same encouraging results.”

Follow-up experiments looked at changes in gene expression after the treatment. The team found that in the treated rats, 136 genes had become more active and 18 became less active, compared to the control group.

The researchers also tested the drug combo on isolated human articular cartilage cells grown in the lab. Similar results followed, showing an increase in molecules that help with cell proliferation and formation of the extra-cellular matrix.

Of course, this doesn’t mean the molecules will necessarily have the same effect in the human body, but it’s a promising step in that direction. The team plans to continue developing the treatment to see if it works in humans, and whether it can prevent osteoarthritis before it develops.

The research was published in the journal Protein & Cell.

Source: Salk Institute