Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice

Abstract

Osteoarthritis (OA) is the leading form of arthritis in the elderly, causing pain, disability, and immobility. OA has been associated with accumulation of senescent cells in or near joints. However, evidence for a causal link between OA and cellular senescence is lacking. Here, we present a novel senescent cell transplantation model involving injection of small numbers of senescent or nonsenescent cells from the ear cartilage of luciferase-expressing mice into the knee joint area of wild-type mice. By using bioluminescence and 18FDG PET imaging, we could track the injected cells in vivo for more than 10 days. Transplanting senescent cells into the knee region caused leg pain, impaired mobility, and radiographic and histological changes suggestive of OA. Transplanting nonsenescent cells had less of these effects. Thus, senescent cells can induce an OA-like state and targeting senescent cells could be a promising strategy for treating OA.

Antiaging effects of bioactive molecules isolated from plants and fungi

“…Senescent cells accumulate in various tissues during aging and contribute to organ dysfunction and the development of chronic disease. As such, injection of senescent cells into the joint is sufficient to induce the development of an osteoarthritis‐like condition in mice . Consistent with these results, elimination of senescent cells using a drug‐inducible transgenic “suicide” gene improved healthspan in genetically‐modified mice .…”

“…As such, injection of senescent cells into the joint is sufficient to induce the development of an osteoarthritis-like condition in mice. 220 Consistent with these results, elimination of senescent cells using a drug-inducible transgenic "suicide" gene improved healthspan in geneticallymodified mice. 221 Based on these observations, the elimination of senescent cells has emerged as a promising strategy to delay aging and reduce age-related diseases.…”

The Clinical Potential of Senolytic Drugs

“…Senescent cells that express the SASP can have substantial local and systemic pathogenic effects. For example, transplanting small numbers of senescent cells around the knee joints of mice induces an osteoarthritis‐like condition resembling the non‐injury‐related osteoarthritis common in elderly humans . Senescent cells also undergo metabolic shifts, including a reduction in fatty acid usage, increases in glycolysis, and reactive oxygen species generation, which can affect other cells and even spread senescence to nearby cells …”

Extracellular vesicles and aging

“…Clearance of senescent cells in versions of this genetic model (INK-ATTAC and 3MR mice) or treating mice with novel senolytics extended healthspan (31,32), restored vascular reactivity (33), stabilized atherosclerotic plaques (34), improved pulmonary function (35), alleviated osteoarthritis (28), improved fatty liver disease (36) and improved lung function in a pulmonary fibrosis model (35). Conversely, injecting senescent cells is able to drive agerelated diseases such as osteoarthritis (37). Thus, the increase in cellular senescence that occurs with aging appears to play a major role in driving life-limiting, agerelated diseases (8,29,30,(38)(39)(40).…”