Dasatinib and quercetin senolytic treatment delays early onset intervertebral disc degeneration in SM/J mice.

Abstract

Genetic background is a major determinant of disc degeneration, a leading cause of chronic back pain and disability. Herein, we demonstrate that premature disc cell senescence contributes to early-onset degeneration in SM/J mice and test two systemic senotherapeutic strategies to mitigate it: Navitoclax (Nav.) and a cocktail of Dasatinib and Quercetin (DQ). While Nav. treatment did not improve severe degeneration in SM/J mice, DQ-treated mice showed lower grades of degeneration and decreased abundance of senescence markers p19^ARF and p21. DQ improved disc cell viability and phenotype retention and retarded fibrosis of the nucleus pulposus tissue. Transcriptomic analysis showed disc compartment-specific effects of the treatment, with cell cycle regulation and JNK signaling being commonly affected across tissue types. A comparison with DQ-mediated aging-dependent amelioration of disc degeneration in C57BL/6N mice identified Junb and Zfp36l1 signaling as shared DQ targets in the mouse disc. This study reinforces the efficacy of senolytic treatments in ameliorating local senescence and intervertebral disc fibrosis.