Treadmill exercise promotes melatonin regulation of TXNIP/NLRP3 and inhibits pyroptosis-mediated osteoarthritis progression in a DMM rat model

Abstract

Osteoarthritis (OA) is characterized by the activation of nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3) by thioredoxin-interacting protein (TXNIP), which promotes inflammation and pyroptosis. This study investigates whether treadmill exercise (TE) enhances melatonin-mediated regulation of the TXNIP/NLRP3 pathway and attenuates OA progression by modulating pyroptosis in a destabilization of the medial meniscus (DMM) rat model. A total of 32 male Sprague-Dawley rats (6 weeks old; 220 ± 20 g) were randomly assigned to four groups: Sham, DMM, DMM + melatonin, and DMM + melatonin + TE. The intervention lasted for 8 weeks. Morphological staining, immunofluorescence (IF), microcomputed tomography with three-dimensional reconstruction, Western blot, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay were used to assess protein and gene expression. Compared with the DMM + melatonin group, the DMM + melatonin + TE group showed greater reductions in cartilage-subchondral bone damage and OA progression through modulation of the pyroptosis pathway. IF staining revealed that TXNIP protein expression was significantly reduced in the DMM + melatonin + TE group. Both the DMM + melatonin and combination treatment groups significantly regulated TXNIP/NLRP3 signaling and inhibited OA progression through pyroptosis. Furthermore, combining TE with melatonin significantly reduced the expression of pyroptotic cytokines compared with the DMM + melatonin group. This study suggests a potential therapeutic approach for managing OA by combining melatonin treatment with moderate TE.

Keywords

Osteoarthritis / Exercise / Melatonin / Thioredoxin-interacting protein / Nucleotide-binding and oligomerization domain-like receptor protein 3

Acknowledgments

None.

Funding

None.

Conflict of interest

The authors declare that they have no competing interests.

Author contributions

Conceptualization: Yongping Wang, Li Chaoyi

Formal analysis: Jamal Alshorman

Investigation: Yongping Wang

Methodology: Ruba Altahla

Writing - original draft: Ruba Altahla, Jamal Alshorman

Writing - review & editing: Ruba Altahla, Jamal Alshorman

Ethics approval and consent to participate

All subjects involved in this study were treated in accordance with the ethical principles outlined in the Declaration of Helsinki, and the study was approved by the ethics committee (No. 2025-M20-21).

Consent for publication

Not applicable.

Availability of data

Data are available from the corresponding author on reasonable request.

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