Senolytic Effect of Navitoclax on Chondrocytes and Synovial Fibroblasts in an Osteoarthritis Murine Model (2023)

Undergraduate: Helen Tran

Faculty Advisor: Brian Diekman
Department: Joint Department of Biomedical Engineering, UNC and NCSU, Thurston Arthritis Research Center, UNC at Chapel Hill

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Cellular senescence is one of the main contributors to aging that occurs when cells enter a stable cell cycle arrest in response to external stress. Thus, the selective clearance of senescent cells has been used as a treatment for age-related diseases, including osteoarthritis (OA). Navitoclax, a common senolytic drug, has been proven to reduce senescent chondrocytes in vitro in murine articular cartilage. This project aims to evaluate the in vitro and in vivo clearance effect of nav on synovial fibroblasts and chondrocytes to reduce senescence burden on OA murine models. Articular cartilage and synovium were isolated from murine knee joints. The tissues were digested and analyzed using flow cytometry. Treatment of nav in vitro was performed using two different dosages, 5 uM and 10 uM, with DMSO 0.1% as a control. Treatment of nav in vivo was performed by delivering 1 mg/ml of nav to the right hindlimb and DMSO to the left hindlimb of each mouse through three intra-articular injections. The in vitro data showed that nav eliminated senescent chondrocytes and synovial fibroblasts for both doses. However, although in vivo treatment of nav reduced the percentage of senescent synovial fibroblasts by half, there was no significant difference between the control and treated groups for chondrocytes. In conclusion, nav demonstrated in vitro clearance effect on both synovial fibroblasts and chondrocytes, and in vivo effect on synovial fibroblasts. Future work is needed to determine the delivery efficiency of nav to the articular cartilage for the elimination of senescent chondrocytes in vivo.

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