researchers ofStanford University School of Medicinediscovered a way to regenerate, in human and mouse tissue, the cushion of cartilage found in joints.
The loss of this slippery, cushioning layer of tissue called articular cartilage is responsible for many cases of joint pain and arthritis, affecting more than 55 million Americans. Nearly 1 in 4 American adults suffer from arthritis, and many more suffer from joint pain and general inflammation.
Stanford researchers have discovered how to regenerate joint cartilage by first causing mild damage to the joint tissue and then using chemical signals to direct the growth of skeletal stem cells as the lesions heal. The work was published on August 17 in the journalnature medicine.
"Cartilage has virtually zero regenerative potential in adulthood, so once it's damaged or lost, what we can do for patients is very limited," said the assistant professor of surgery.Carlos K. F. Chan, Doctor. "It's extremely rewarding to find a way to help the body regenerate this important tissue."
The work builds on previous research at Stanford that resulted in the isolation of the skeletal stem cell, a self-renewing cell that is also responsible for making bone, cartilage, and a special type of cell that helps blood cells form. develop in the bone marrow. . The new research, like previous findings from mice and human skeletal stem cells, was carried out primarily in the labs of Chan and the professor of surgery.Michael Longaker, MD.
Articular cartilage is a complex and specialized tissue that provides soft, elastic cushioning between the bones of the joints. When this cartilage is damaged by trauma, disease, or simply thins with age, the bones can rub directly against each other, causing pain and inflammation, which can eventually lead to arthritis.
Damaged cartilage can be treated with a technique called microfracture, in which small holes are drilled into the surface of a joint. The microfracture technique causes the body to create new tissue in the joint, but the new tissue is not very similar to cartilage.
"Microfracture results in what's called fibrocartilage, which actually looks more like scar tissue than natural cartilage," Chan said. "It covers the bone and is better than nothing, but it lacks the rebound and elasticity of natural cartilage and tends to break down relatively quickly."
The latest research came about, in part, thanks to the work of surgeon Matthew Murphy, PhD, a visiting fellow at Stanford who is now at the University of Manchester. “I never felt like anyone really understood how microfracturing really worked,” Murphy said. "I realized that the only way to understand the process was to look at what the stem cells do after the microfracture." Murphy is the lead author of the article. Chan and Longaker are co-senior authors.
For a long time, Chan said, people assumed that adult cartilage did not regenerate after injury because the tissue did not have many skeletal stem cells that could be activated. Working in a mouse model, the team documented that microfracture activated skeletal stem cells. However, if left alone, these activated skeletal stem cells regenerate fibrocartilage in the joint.
But what if the healing process after microfracture could be directed toward cartilage development and away from fibrocartilage? The researchers knew that as bone develops, cells must first go through a cartilage stage before becoming bone. They had the idea that they could encourage skeletal stem cells in the joint to start a pathway to becoming bone, but stop the process at the cartilage stage.
The researchers used a powerful molecule called bone morphogenetic protein 2 (BMP2) to initiate bone formation after a microfracture, but stopped the process halfway with a molecule that blocked another important signaling molecule in bone formation, called factor vascular endothelial growth (VEGF).
"What we got was cartilage made from the same cell type as natural cartilage with comparable mechanical properties, unlike the fibrocartilage we normally get," Chan said. "It also restored mobility in osteoarthritic mice and significantly reduced pain."
As proof-in-principle that this could work in humans as well, the researchers transferred human tissue into mice that were bred not to reject the tissue and were able to show that human skeletal stem cells can go toward bone development but stop at cartilage. . Practices.
The next step in the research is to perform similar experiments on larger animals before beginning human clinical trials. Murphy notes that because of the difficulty of working with very small mouse joints, there might be some improvements to the system that they could make as they move toward relatively larger joints.
The first human clinical trials may be for people with arthritis in the fingers and toes. “We can start with small joints, and if that works, move to larger joints like the knees,” says Murphy. “Currently, one of the most common surgeries for arthritis in the fingers is to remove the bone at the base of the thumb. In those cases, we can try to save the joint, and if that doesn't work, we just remove the bone like we would anyway. There is a lot of potential for improvement, and the downside is that we would be back to where we were before.”
Longaker points out that one advantage of his discovery is that the key components of a potential therapy are approved as safe and effective by the FDA. "BMP2 has already been approved to help with bone healing, and VEGF inhibitors are already used as cancer therapies," Longaker said. "That would help speed up the approval of any therapy we develop."
Joint replacement surgery has revolutionized the way doctors treat arthritis and is very common: by age 80, 1 in 10 people will have a hip replacement and 1 in 20 will have a knee replacement. But this joint replacement is extremely invasive, has a limited lifespan, and is done only after arthritis has started and patients are enduring prolonged pain. The researchers say they can foresee a time when people will be able to avoid arthritis in the first place by rejuvenating joint cartilage before it severely degrades.
"One idea is to follow a 'Jiffy Lube' model of cartilage replacement," Longaker said. "You don't wait for the damage to accumulate; you go in periodically and use this technique to grow the cartilage in the joint before you have a problem."
Longaker is the Deane P. and Louise Mitchell Professor in the School of Medicine and co-director of the Institute for Stem Cell Biology and Regenerative Medicine. Chan is a member of Stanford's Institute for Stem Cell Biology and Regenerative Medicine and Immunology.
Other Stanford scientists who participated in the research included the Irving Weissman Professor of Pathology, MD, the Virginia Professor, and D.K. Ludwig in Clinical Research in Cancer Research; Stuart B. Goodman, MD, professor of surgery, Robert L. and Mary Ellenburg Professor of Surgery; associate professor of orthopedic surgery Fan Yang, PhD; professor of surgery Derrick C. Wan, MD; instructor in orthopedic surgery Xinming Tong, PhD; postdoctoral researcher Thomas H. Ambrosi, PhD; visiting postdoctoral researcher Liming Zhao, MD; life science research professionals Lauren S. Koepke and Holly Steininger; MD/PhD Student Gunsagar S. Gulati, PhD; graduate student Malachia Y. Hoover; former student Owen Marecic; former medical student Yuting Wang, MD; and director of the scanning probe microscopy laboratory, Marcin P. Walkiewicz, PhD.
The research was supported by the National Institutes of Health (grants R00AG049958, R01 DE027323, R56 DE025597, R01 DE026730, R01 DE021683, R21 DE024230, U01HL099776, U24DE026914, R21 DE019274, NIGMS K08GM109105, NIH R01GM123069 and NIH1R01AR071379), the California Institute for Regenerative Medicina, Oak Foundation, Pitch Johnson Fund, Gunn/Olivier Research Fund, Stinehart/Reed Foundation, Siebel Foundation, Howard Hughes Medical Institute, German Research Foundation, PSRF National Endowment, National Center for Research Resources, a Fundação de Pesquisa do Câncer de Próstata , una Federación Americana de Pesquisa do Envelhecimento y una Fundación Nacional de Pesquisa da Artrite.