Reprogramming Genes to Keep Joints Healthy

Knee Joint
Image Source: NIH Director’s Blog

By: Dr. Francis Collins

Our joints are pretty amazing marvels of engineering, but they don’t last forever. As we age, or if we suffer certain injuries, the smooth, slippery white cartilage covering the ends of our bones begins to fray and degrade. This causes osteoarthritis (OA), or ‘wear-and-tear’ arthritis. As the cartilage thins and disappears, the bones can even grow spurs that grate against each other, causing swelling and pain. It’s a major cause of disability, and there’s currently no cure—other than joint replacement, which is a pretty big deal and isn’t available for all joints. About 27 million Americans already have osteoarthritis; about 1 in 2 will suffer from some form of the disease over their lifetime. Those are lousy odds.

So I was excited when I read about an NIH-funded study describing a protein that prevents age-related and injury-induced OA—in mice. The researchers, based at the Baylor College of Medicine and the Howard Hughes Medical Institute, focused on a protein called lubricin.

Children with a rare genetic form of OA have a mutation in the proteoglycan 4 (PRG4) gene, which then produces less lubricin. Lubricin, as the name suggests, lubricates joints and the cartilage—and is produced by the same cells that build cartilage.

The researchers figured that if too little lubricin was associated with arthritis in these kids, perhaps a bit extra of it would slow down or prevent the disease. So they genetically engineered mice to cause them to produce abnormally large amounts of lubricin throughout development and adulthood. Then, using a powerful new imaging technique called phase contrast-micro-CT, they found that the cartilage and skeleton in these high-lubricin mice appeared exceptionally healthy, and they were protected against age-related OA.

Moreover, the engineered mice also seemed to respond to injury better. When the researchers studied mice with an anterior cruciate ligament (ACL) tear—a common, and sometimes career ending, knee injury in athletes—the normal mice showed signs of injury-triggered OA: the quantity of cartilage covering the bone had shrunk and the animals moved less well. The mice with extra lubricin, on the other hand, seemed resistant to OA and were almost indistinguishable from normal, uninjured mice.

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