Senescence cell–associated extracellular vesicles serve as osteoarthritis disease and therapeutic markers
Ok Hee Jeon, David R. Wilson, Cristina C. Clement, Sona Rathod, Christopher Cherry, Bonita Powell, Zhenghong Lee, Ahmad M. Khalil, Jordan J. Green, Judith Campisi, Laura Santambrogio, Kenneth W. Witwer, Jennifer H. Elisseeff
Ok Hee Jeon, David R. Wilson, Cristina C. Clement, Sona Rathod, Christopher Cherry, Bonita Powell, Zhenghong Lee, Ahmad M. Khalil, Jordan J. Green, Judith Campisi, Laura Santambrogio, Kenneth W. Witwer, Jennifer H. Elisseeff
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Research Article Aging Therapeutics

Senescence cell–associated extracellular vesicles serve as osteoarthritis disease and therapeutic markers

Abstract

Senescent cells (SnCs) are increasingly recognized as central effector cells in age-related pathologies. Extracellular vesicles (EVs) are potential cellular communication tools through which SnCs exert central effector functions in the local tissue environment. To test this hypothesis in a medical indication that could be validated clinically, we evaluated EV production from SnCs enriched from chondrocytes isolated from human arthritic cartilage. EV production increased in a dose-responsive manner as the concentration of SnCs increased. The EVs were capable of transferring senescence to nonsenescent chondrocytes and inhibited cartilage formation by non-SnCs. microRNA (miR) profiles of EVs isolated from human arthritic synovial fluid did not fully overlap with the senescent chondrocyte EV profiles. The effect of SnC clearance was tested in a murine model of posttraumatic osteoarthritis. miR and protein profiles changed after senolytic treatment but varied depending on age. In young animals, senolytic treatment altered expression of miR-34a, -30c, -125a, -24, -92a, -150, and -186, and this expression correlated with cartilage production. The primary changes in EV contents in aged mice after senolytic treatment, which only reduced pain and degeneration, were immune related. In sum, EV contents found in synovial fluid may serve as a diagnostic for arthritic disease and indicator for therapeutic efficacy of senolytic treatment.

Authors

Ok Hee Jeon, David R. Wilson, Cristina C. Clement, Sona Rathod, Christopher Cherry, Bonita Powell, Zhenghong Lee, Ahmad M. Khalil, Jordan J. Green, Judith Campisi, Laura Santambrogio, Kenneth W. Witwer, Jennifer H. Elisseeff

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Figure 3

miRs carried by EVs are differentially present in OA synovial fluid from young versus aged mice after clearance of SnCs.

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miRs carried by EVs are differentially present in OA synovial fluid from...
(A) Quantification of miR-34a-5p, miR-128a-3p, and miR-146a-5p in young and aged PTOA mice treated with vehicle (veh) or the senolytic UBX0101, which can mediate senescence and the SASP, 28 days after ACLT surgery. All data are expressed as mean ± SEM, and each data point represents an individual mouse. One-way ANOVA with Tukey’s multiple-comparisons test was used for statistical analysis (young, n = 4; aged, n = 5). *P < 0.05. (B) Workflow of analysis of EVs from the synovial fluid of PTOA mice treated with veh or UBX0101. (C and D) Plots illustrating the fold change (UBX0101/veh; x axis) and significance level expressed as the log P value (y axis). The blue circles represent miRs that were upregulated and red circles represent miRs that were downregulated by UBX0101 compared with veh-treated PTOA young (C) and aged (D) mice (n = 3 per group). Significance was determined based on a P value cutoff of 0.05. (E) The heatmap reveals significant correlations among mmu-miR-30c-5p, -92a-3p, -24-3p, -186-5p, -125a-5p, and -150-5p, expression of which was significantly altered by UBX0101 treatment in young PTOA mice and the signaling pathways in which they are predicted by the DIANA-miRPath (v3.0) to participate.