The USP5-MATN3 axis in nucleus pulposus cell senescence: A Deubiquitination mechanism protecting against intervertebral disc degeneration.

Abstract

Intervertebral disc degeneration (IVDD) is a major cause and independent risk factor for low back pain. This study aims to explore the molecular mechanisms underlying IVDD and provide new ideas for targeted treatment. Cellular senescence is a key pathological event in IVDD, but its upstream regulatory network in nucleus pulposus cells (NPCs) remains unclear. This study found that MATN3 protein expression decreased significantly during IVDD, and its level was closely associated with NPC senescence. Functionality experiment data show that overexpression of MATN3 can effectively inhibits NPC senescence in vitro and delays the pathological progression of IVDD in a rat tail puncture model. Interestingly, no significant difference was observed in MATN3 at the mRNA level. Mechanistically, immunoprecipitation-mass spectrometry and co-immunoprecipitation identified USP5 as a direct interacting protein of MATN3, which it stabilized via deubiquitination, and functional rescue experiments confirmed that USP5 alleviated NPC senescence by upregulating MATN3. In conclusion, this study clarifies the molecular mechanism by which the USP5/MATN3 axis regulates cellular senescence and affects IVDD progression, opening up new potential targets for the intervention strategy of IVDD.