Senolytic Drug Combination Delays Early Intervertebral Disc Degeneration in Mice

Targeting senescent cells with dasatinib–quercetin preserves disc structure and modulates degeneration-associated pathways in a mouse model

CHINA, May 25, 2026 /EINPresswire.com/ -- Early-onset intervertebral disc degeneration is partly driven by cellular senescence, yet effective disease-modifying therapies remain limited. Researchers report that the senolytic combination dasatinib and quercetin reduces senescence markers, inflammatory signaling, and degenerative tissue changes in a genetic mouse model of disc disease. In contrast, navitoclax shows no benefit. The study identifies JNK (c-Jun N-terminal kinase) signaling as a key pathway underlying disease progression and therapeutic response, highlighting a potential strategy for slowing spinal disc degeneration.

Intervertebral disc degeneration is a major cause of chronic back and neck pain, yet current treatments largely focus on symptom relief rather than preventing disease progression. A growing body of evidence suggests that cellular senescence, where cells lose proliferative capacity and secrete inflammatory factors, plays a central role in accelerating disc tissue breakdown. However, how genetic susceptibility influences early disease onset and whether senescence-targeting therapies can alter this trajectory has remained poorly understood.

To address this challenge, a research team led by the James J. Maguire Jr. Professor Makarand V. Risbud from the Department of Orthopaedic Surgery at Sidney Kimmel Medical College, Thomas Jefferson University, USA, investigated whether senolytic therapies could delay degeneration in SM/J mice, a model of spontaneous early-onset disc disease. The researchers compared two approaches: navitoclax, which targets BCL-2 family survival proteins, and a combination of dasatinib and quercetin (DQ), a widely studied senolytic cocktail. Their findings were published on April 14, 2026, in Volume 14 of the journal Bone Research.

Using histological, molecular, imaging, and transcriptomic analyses, the team systematically evaluated structural, cellular, and molecular changes in intervertebral discs over time. They found that SM/J mice exhibited elevated senescence markers as early as four weeks of age, preceding overt structural degeneration. This early senescence burden was accompanied by inflammatory activation and gene expression changes linked to stress and extracellular matrix remodeling.

“Importantly, early molecular changes preceded visible tissue damage, suggesting that senescence is not just a consequence of degeneration but a driving force in genetically susceptible discs,” explained Prof. Risbud.

Treatment with dasatinib–quercetin significantly reduced disc degeneration severity compared with untreated controls. Mice receiving DQ showed improved preservation of nucleus pulposus structure, reduced degenerative remodeling, lower expression of senescence markers such as p19ARF and p21, and decreased inflammatory signaling. Importantly, these benefits were not observed to the same extent with navitoclax, which failed to improve either molecular or structural outcomes.

A deeper transcriptomic analysis revealed that DQ treatment reshaped gene expression programs related to inflammation, stress responses, and cell cycle regulation, consistent with reduced senescence and improved tissue homeostasis. Further computational and functional analyses implicated JNK (c-Jun N-terminal kinase) signaling as a central pathway associated with disease progression and therapeutic response.

“These data point to JUN signaling as a convergence hub linking senescence, inflammation, and extracellular matrix breakdown, helping explain why pathway-specific modulation by dasatinib–quercetin is effective,” Prof. Risbud noted.

Functional experiments using human degenerated disc cells supported these findings. Inhibition of JUN signaling recapitulated key effects of DQ treatment, reducing senescence-associated β-galactosidase activity and lowering inflammatory gene expression. These results suggest that JUN signaling may act as a regulatory hub connecting senescence, inflammation, and tissue degeneration in the intervertebral disc.

Beyond mechanistic insights, the study highlights broader implications for musculoskeletal aging and regenerative medicine. In the short term, these findings improve understanding of how genetic susceptibility interacts with cellular senescence to drive early disc degeneration. In the longer term, they may guide development of targeted senotherapeutic strategies aimed at slowing disease progression in at-risk individuals before irreversible tissue damage occurs.

The research also underscores that senolytic efficacy is highly context-dependent, with different drugs producing distinct outcomes depending on tissue type and underlying molecular pathways. This could influence future therapeutic design, shifting attention toward pathway-specific interventions rather than broad senescent cell elimination.

Overall, the study provides preclinical evidence that dasatinib–quercetin can delay early disc degeneration by suppressing senescence-associated pathways, preserving disc structure, and reducing inflammation and fibrotic tissue changes, with JUN signaling emerging as a potential therapeutic target.

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Reference
Title of original paper: Dasatinib and quercetin senolytic treatment delays early onset intervertebral disc degeneration in SM/J mice
Journal: Bone Research
DOI: 10.1038/s41413-026-00526-4

About Thomas Jefferson University, USA
Thomas Jefferson University, located in Philadelphia, USA, is a nationally recognized academic health sciences institution known for its excellence in medical education, biomedical research, and clinical innovation. The university integrates advanced research with patient-centered healthcare through its renowned Sidney Kimmel Medical College and affiliated hospitals. It fosters interdisciplinary collaboration across medicine, engineering, and life sciences to address complex health challenges. With a strong emphasis on translational research, Jefferson advances discoveries from laboratory to clinical application, particularly in areas such as cancer, neuroscience, and musculoskeletal disorders. The institution is committed to improving health outcomes locally and globally.
Website: https://www.jefferson.edu/

About Professor Makarand V. Risbud from Thomas Jefferson University
Prof. Makarand V. Risbud is the James J. Maguire Jr. Professor of Spine Research and Director of Orthopedic Research at Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, USA. He earned his PhD from the National Center for Cell Science, India in 2001, followed by postdoctoral training at Harvard University from 2001 to 2002. His research focuses on intervertebral disc biology, particularly nucleus pulposus cell adaptation to hypoxia and osmotic stress. He investigates transcriptional regulators, alongside regenerative strategies using mesenchymal stem cells. His work is highly translational, aiming to develop therapies for disc degeneration and spine disorders.

Funding Information
This study is supported by the grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) R01AR055655, R01AR064733, and R01AR074813, and the Michael Michelson Gift Fund to MVR. EJN received a PhD fellowship (PD/BD/128077/2016) from the MD/PhD Program at the University of Minho, funded by the Fundação para a Ciência e a Tecnologia (FCT).

Yini Bao
Bone Research Editorial Office
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