In a preclinical study in mice and human cells, researchers report that selectively removing old or 'senescent' cells from joints could stop and even reverse the progression of osteoarthritis.
The findings, published in Nature Medicine, support growing evidence that senescent cells contribute to age-related diseases and demonstrate that using drug therapies to remove them from the joint not only reduces the development of post-traumatic osteoarthritis, but creates an environment for new cartilage to grow and repair joints.
Senescent cells accumulate in tissues as we age and are a normal part of wound healing and injury repair. They secrete important signals that call immune cells and other cell types into damaged tissue so they can clean up and rebuild. However, in articular joints such as the knee, and cartilage tissue in particular, these senescent cells often are not cleared from the area after injury. Their prolonged presence causes a cascade of events, which starts the development of osteoarthritis.
"Combine age-related increases in senescent cells, plus trauma, and it's a double whammy," says the senior author.
The researchers took young mice and performed surgery on them, cutting their anterior cruciate ligaments (ACL) to mimic injury. The researchers then administered injections of an experimental drug named UBX0101, which was recently identified to kill senescent cells in laboratory studies.
Researchers injected UBX0101 into the mice's joints 14 days after trauma, when degradation was already starting, and observed that the presence of senescent cells was reduced by roughly 50 percent. In addition, the researchers monitored gene expression in treated mice and found that genes associated with reparative cartilage growth were activated in the joint after treatment.
Similar experiments were conducted in older mice, which showed some key differences from the treatment in younger mice. The older mice had thinner cartilage in the joint and increased pain levels before the experiment. After treatment with UBX0101 injections, the older mice exhibited reduced pain like their more youthful counterparts, but did not exhibit signs of cartilage regeneration.
To gauge the potential for UBX0101 to be translated to a human treatment, researchers tested the drug in cultures of human cartilage cells taken from donors with clinically severe osteoarthritis (i.e. patients who had undergone a total knee replacement surgery due to damage from osteoarthritis). The group then grew these cartilage cells into 3D structures in the lab. The 3D structures mimic how cartilage tissues grow in the body They then exposed these cells to UBX0101 for four days. The researchers observed that not only were the number of senescent cells dramatically reduced, but the tissue derived from these patients began forming new cartilage after the elimination of senescent cells.
"What was most striking about the results in human tissue is the fact that removal of senescent cells had a profound effect on tissue from very advanced osteoarthritis patients, suggesting that even patients with advanced disease could benefit," says the author.
Although the treatment appears promising, one limitation in the current study is the short time that UBX101 remains in the joint. However, Unity Biotechnology, who co-developed UBX0101, is working on single-injection formulations. The researchers are hopeful that with further development, UBX0101 may one day offer a one-dose treatment for osteoarthritis.
Clearing out old cells could extend joint health, stop osteoarthritis
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