Senotherapeutics for Knee Osteoarthritis

Osteoarthritis (OA) is a chronic disease that imposes a significant economic burden and deteriorates quality of life. Nevertheless, current therapeutic options for OA are limited to symptomatic remedies. As such, there is a high interest in novel methods for treating or preventing OA. One of the most promising medication modalities is through the clearance of cells that are cell cycle arrested but resistant to apoptosis, termed senescent cells. Additionally, these cells are also resistant to alternative programmed cell death modes, such as ferroptosis and pyroptosis. Senescent cells tend to accumulate with age due to increasing cellular and genetic damage. These cells can release inflammatory factors and signaling molecules termed senescence-associated secretory phenotype (SASP). In addition to triggering an inflammatory milieu in joints, SASP can also induce senescence in other cells through autocrine signaling. It has been shown via in vitro and in vivo tests that clearance of senescent cells through a class of drugs known as senolytics, or neutralization of SASP with senomorphics, can improve OA pathogenesis. Following these results, several clinical trials have been conducted to evaluate the efficacy of senotherapeutics against knee OA. Yet there remains a need for a comprehensive assessment of safety and optimization of senotherapeutic treatment regimens for knee OA. To this end, a better understanding of molecular mechanisms behind chondrocyte senescence and knee OA pathogenesis is necessary. Identification of novel compounds that can specifically target chondrocyte senescence pathways can assist in developing more effective therapies against OA.