Restoration of lysosomal function attenuates autophagic flux impairment in nucleus pulposus cells and protects against mechanical overloading-induced intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain that incurs large socioeconomic burdens. Growing evidence reveals that macroautophagy/autophagy dysregulation contributes to IVDD, but the exact role of autophagy and its regulatory mechanisms remain largely unknown. Here, we found that mechanical overloading impaired the autophagic flux of nucleus pulposus (NP) cells in vivo and in vitro. Mechanistically, the impairment of autophagic flux was attributed to lysosomal dysfunction induced by overloading. Overloading could also lead to lysosomal membrane permeabilization and consequent lysosome-dependent cell death. As critical effectors of lysosomal quality control pathways, CHMP4B (charged multivesicular body protein 4B) and TFEB (transcription factor EB) were downregulated in overloading-treated NP cells and degenerative discs. Restoring lysosomal function by CHMP4B or TFEB overexpression attenuated autophagic flux impairment of NP cells and protected against overloading-induced IVDD. Additionally, human IVDD was associated with impaired autophagy, and defective lysosomal quality control was also linked to human IVDD. Collectively, these findings highlighted that lysosomal defects were crucial for mechanical overloading-induced autophagic flux impairment and death of NP cells, suggesting the potential therapeutic relevance of restoring lysosomal function for IVDD.