Bone marrow mesenchymal stem cell-derived exosomes ameliorate intervertebral disc degeneration by regulating HMGB1 acetylation via SIRT6.

BACKGROUND

Intervertebral disc degeneration (IVDD) is a leading cause of low back and leg pain and is primarily driven by inflammation-induced apoptosis of nucleus pulposus (NP) cells. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-exos) have shown strong therapeutic potential for degenerative diseases. Sirtuin 6 (SIRT6), a key regulator of aging and inflammation, has been closely associated with IVDD progression. Therefore, we hypothesized that BMSC-exos might alleviate IVDD by promoting SIRT6-mediated deacetylation of high mobility group box 1 (HMGB1), thereby suppressing inflammation.

METHODS

In the present study, BMSC-exos were isolated from BMSCs and characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot analysis. The mechanisms by which BMSC-exos regulate the SIRT6/HMGB1/Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling pathway were investigated using Cell Counting Kit-8 (CCK-8) assay, reverse transcription-quantitative polymerase chain reaction, western blotting, ELISA, and immunofluorescence analysis. The therapeutic efficacy of BMSC-exos in vivo was evaluated by hematoxylin and eosin (H&E) staining, ELISA, immunofluorescence staining, and TUNEL assays.

RESULTS

BMSC-exos upregulated SIRT6 expression, promoted HMGB1 deacetylation, and prevented the nuclear-to-cytoplasmic translocation of HMGB1, thereby inhibiting activation of the HMGB1/TLR4/NF-κB signaling pathway, alleviating inflammation in IVDD, and protecting NP cells in vitro. Furthermore, BMSC-exos suppressed inflammatory responses, reduced NP cell apoptosis, and attenuated IVDD progression in vivo.

CONCLUSIONS

To our knowledge, this study provides the first evidence that BMSC-exos inhibit inflammation by regulating the SIRT6/HMGB1/TLR4/NF-κB pathway, thereby attenuating IVDD progression.