Although senescent cells (SnCs) are a normal part of wound healing and injury repair, they can overstay their welcome in joints. These cells secrete factors that are useful, up to a point, but if they linger, they can bring about a cascade of molecular events and even start the development of osteoarthritis (OA). Yet clearing SnCs from joints could prevent joint degradation. This idea was put to the test in animal studies conducted by scientists based at Johns Hopkins University.
The scientists, led by Jennifer Elisseeff, Ph.D., 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 SnCs in laboratory studies. Similar experiments were conducted in older mice.
The results of these interventions were described in a paper (“Local Clearance of Senescent Cells Attenuates the Development of Post-Traumatic Osteoarthritis and Creates a Pro-Regenerative Environment”) that appeared April 24 in the journal Nature Medicine. According to the paper’s authors, their work has added to the accumulation of evidence that SnCs contribute to age-related diseases. Most important, the scientists assert that using drug therapies to remove SnCs from the joint not only reduces the development of post-traumatic OA, but also creates an environment for new cartilage to grow and repair joints.
“To test the idea that SnCs might play a causative role in OA, we used the p16-3MR transgenic mouse,” wrote the article’s authors. “This mouse strain allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT).
“We found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development.”
Researchers injected UBX0101 into the mice's joints 14 days after trauma, when degradation was already starting and observed that the presence of SnCs was reduced by roughly 50%. 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.
The younger and the older mice showed some key differences. The older mice had thinner cartilage in the joint and increased pain levels before the experiment. Also, 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 OA (i.e., patients who had undergone a total knee replacement surgery due to damage from OA). Elisseeff's group then grew these cartilage cells into 3D structures in the lab. The 3D structures mimic how cartilage tissues grow in the body, Elisseeff explains. They then exposed these cells to UBX0101 for 4 days. The researchers observed that not only were the number of SnCs dramatically reduced, but the tissue derived from these patients began forming new cartilage after the elimination of SnCs.
“Intra-articular injection of a senolytic molecule that selectively killed SnCs validated these results in transgenic, non-transgenic and aged mice,” the authors summarized. “Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins.”
Although the treatment appears promising, Dr. Elisseeff cautioned that 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 OA. Dr. Elisseeff explained, “Because the drug targets and kills the SnCs directly, once they are eliminated, patients will not need to return for frequent treatments.”
“What was most striking about the results in human tissue is the fact that removal of SnCs had a profound effect on tissue from very advanced OA patients, suggesting that even patients with advanced disease could benefit,” said Dr. Elisseeff.