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

TL;DR

Senolytic treatment with Dasatinib and Quercetin delays disc degeneration in mice by reducing cell senescence and fibrosis.

Contribution

The study identifies Dasatinib and Quercetin as effective senolytic agents for mitigating early-onset disc degeneration in SM/J mice.

Findings

DQ treatment reduced senescence markers and disc degeneration in SM/J mice.

DQ improved disc cell viability and reduced nucleus pulposus fibrosis.

Transcriptomic analysis revealed cell cycle and JNK signaling as common targets of DQ treatment.

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 p19ARF 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.

Figures