Cartilage is grown in the arthritic joints of mice

By Gina Kolata

The painful knees and hips experienced by so many people with osteoarthritis result from a loss of cartilage, which serves as a sort of cushioning in the joints. It had long been thought that cartilage, once gone, cannot grow back.

Now researchers at Stanford University have grown new cartilage in the joints of arthritic mice. Primitive cells that can be transformed into new cartilage lie dormant at the ends of bones, the researchers reported in Nature Medicine. The cells just have to be awakened and stimulated to grow.

The researchers say the next step is to try to grow cartilage in larger animals, like dogs or pigs. They are optimistic that the finding could eventually lead to treatments to prevent the often debilitating pain that arises when cartilage erodes away.

“It is really a major advance in field of osteoarthritis,” said Dr. Gerard Karsenty, a bone specialist at Columbia University who was not involved in the research.

Although scientists often question whether findings in mice may apply to humans, diseases of the skeleton often do, he added.

“When you demonstrate something in the mouse, I don’t know of any example where it has not applied to humans,” Karsenty said.

But Dr. Robert Marx, an orthopedic surgeon at the Hospital for Special Surgery in Manhattan, cautions that the path to a treatment that helps patients may be long and unpredictable.

Scientists will need to determine not only whether the method is safe and effective but also to learn which patients are likely to be helped — those early or later in the course of arthritis — and how long the treatment will last.

An estimated 50 million Americans have osteoarthritis; the lifetime risk of getting the diagnosis is 40%. Once the degeneration of the cartilage lining a joint begins, there is no treatment available to restore it.

The new research was conducted with mice with knee arthritis and with human bone transplanted into mice. Normal cartilage was grown in both settings.

The mice had knee arthritis so severe they had trouble walking. After they grew new cartilage, they stopped limping and grimacing (mice are known to have facial expressions indicating pain).

The study began with a discovery in 2018 by Charles Kwok Fai Chan, then a postdoctoral student at Stanford and now an assistant professor in the surgery department. He found primitive cells — stem cells — at the ends of bones that can give rise to cartilage, bone marrow or bone, depending on how they are stimulated.

But those stem cells were not dividing or growing. Their dormancy, Chan realized, was why bone experts had assumed cartilage, once lost, could not return. The challenge was to find a way to awaken those stem cells and direct them to form cartilage.

He; Dr. Michael T. Longaker, who directs the program in regenerative medicine at Stanford; and their colleagues discovered how to do so in three steps.

First, the scientists slightly damaged the ends of bone by drilling tiny holes in it. This technique — microfracture — is sometimes used by orthopedic surgeons to relieve pain in arthritic joints. The drilling is done through a scope, and the holes are minuscule.

The procedure resulted in the growth of tough scar tissue, which the researchers realized had occurred because the bone’s stem cells had awakened and had turned into this tough tissue. The tissue does not cushion the joint and does not last long, Longaker said. But it can help with pain, so may serve as a stopgap measure.

The researchers wanted to turn those awakened stem cells into cartilage. The recipe that worked was to treat the stem cells with bone morphogenetic protein, which is used to help fuse bones.

The scientists also used a drug called Avastin, which prevents the stem cells from getting a blood supply. Unlike bone and bone marrow, cartilage has no blood supply, and the drug helped stimulate the stem cells to turn into cartilage.

The investigators provided the drugs directly to the ends of bones, putting them in a gel.

The cartilage that grew in the mice not only looked like normal but lasted for four months, a quarter of the animals’ lifetimes. Chan and Longaker envision a time when doctors will be able to “resurface” arthritic joints or, even better, to treat people who are just beginning to develop arthritis, perhaps staving off the sort of damage that even joint replacements cannot fix.

If the strategy works in humans, then early treatment may be the best approach, Marx said.

“Arthritis deforms joints and changes bones,” he said. By the time people have hips or knees replaced, irreversible damage may be done. Legs may be bowed, bones damaged.

“You cannot totally turn back the clock,” Marx said. At that point, he said, “adding cartilage will not fix it.”

He worries, though, that orthopedists may not wait for rigorous studies — the method of awakening the dormant cells is relatively simple, and the drugs required are already on the market.

Faced with a patient with aching knees, orthopedists may be tempted to say, “Let’s try this. You don’t have much to lose,” Marx noted.

“That’s the problem with a lot of things in orthopedics,” he added. “There is typically widespread adoption before there is evidence.”