A small molecule dubbed kartogenin encourages stem cells to take on the characteristics of cells that make cartilage, a new study shows. And treatment with kartogenin allowed many mice with arthritis-like cartilage damage in a knee to regain the ability to use the joint without pain.
The findings provide new clues in the long-running effort to find ways to regenerate cartilage, a central puzzle in the battle against osteoarthritis, scientists report online April 5 in Science.
The new approach taps into mesenchymal stem cells, which naturally reside in cartilage and give rise to cells that make connective tissue. These include chondrocytes, the only cells in the body that manufacture cartilage. Kartogenin steers the stem cells to wake up and take on cartilage-making duties. This is an essential step in the cartilage repair that falls behind in people with osteoarthritis, the most common kind of arthritis, which develops from injury or long-term joint use.
“In the blue-sky scenario, this would be a locally delivered therapy that would target stem cells already there,” says study coauthor Kristen Johnson, a molecular biologist at the Genomics Institute of the Novartis Research Foundation in San Diego.
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Johnson and her colleagues screened 22,000 compounds in cartilage and found that one, kartogenin, induced stem cells to take on the characteristics of chondrocytes. The molecule turned on genes that make cartilage components called aggrecan and type II collagen. Tests of mice with cartilage damage similar to osteoarthritis showed that kartogenin injections lowered levels of a protein called cartilage oligomeric matrix protein. People with osteoarthritis have an excess of the protein, which is considered a marker of disease severity. Kartogenin also enabled mice with knee injuries to regain weight-bearing capacity on the joint within 42 days.
Lab work revealed that kartogenin inhibits a protein called filamin A in the mesenchymal stem cells. This unleashes other compounds that can then orchestrate the activity of genes useful in turning the stem cells into functional chondrocytes. In so doing, Johnson says, kartogenin seems to protect and repair cartilage.
Millions of people develop osteoarthritis as they reach old age. Cartilage serves as the shock absorber of the skeleton, but surgery to clean out torn cartilage has limited success, as does surgery to induce growth of a fibrous kind of coating at the ends of bones that have lost their natural cartilage caps. This losing battle leaves bone-on-bone friction, inflammation and pain.
“Our cartilage wasn’t meant to live this long,” says molecular biologist Mary Goldring of Weill Cornell Medical College in New York. A cartilage imbalance results from wear and tear, literally, as people age, she says. Regenerating the cartilage-making process in the body has become a primary goal in orthopedic medicine.