Impact of autophagy inhibition on intervertebral disc cells and extracellular matrix.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38234974.
- Also identified by DOI 10.1002/jsp2.1286 and PMC identifier 10792703.
- Licence recorded as CC BY-NC-ND.
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Abstract
Intervertebral disc degeneration (IDD) is a leading contributor to low back pain (LBP). Autophagy, strongly activated by hypoxia and nutrient starvation, is a vital intracellular quality control process that removes damaged proteins and organelles to recycle them for cellular biosynthesis and energy production. While well-established as a major driver of many age-related diseases, autophagy dysregulation or deficiency has yet been confirmed to cause IDD. In vitro, rat nucleus pulposus (NP) cells treated with bafilomycin A1 to inhibit autophagy were assessed for glycosaminoglycan (GAG) content, proteoglycan synthesis, and cell viability. In vivo, a transgenic strain (<i>Col2a1-Cre</i>; <i>Atg7</i> <sup><i>fl/fl</i></sup>) mice were successfully generated to inhibit autophagy primarily in NP tissues. <i>Col2a1-Cre</i>; <i>Atg7</i> <sup><i>fl/fl</i></sup> mouse intervertebral discs (IVDs) were evaluated for biomarkers for apoptosis and cellular senescence, aggrecan content, and histological changes up to 12 months of age. Here, we demonstrated inhibition of autophagy by bafilomycin produced IDD features in the rat NP cells, including increased apoptosis and cellular senescence (<i>p21</i> <sup><i>CIP1</i></sup>) and decreased expression of disc matrix genes <i>Col2a1</i> and <i>Acan</i>. H&E histologic staining showed significant but modest degenerative changes in NP tissue of <i>Col2a1-Cre; Atg7</i> <sup><i>fl/fl</i></sup> mice compared to controls at 6 and 12 months of age. Intriguingly, 12-month-old <i>Col2a1-Cre; Atg7</i> <sup><i>fl/fl</i></sup> mice did not display increased loss of NP proteoglycan. Moreover, markers of apoptosis (cleaved caspase-3, TUNEL), and cellular senescence (p53, <i>p16</i> <sup><i>INK4a</i></sup> <i>,</i> IL-1β, TNF-α) were not affected in 12-month-old <i>Col2a1-Cre; Atg7</i> <sup><i>fl/fl</i></sup> mice compared to controls. However, <i>p21</i> <sup><i>CIP1</i></sup>and <i>Mmp13</i> gene expression were upregulated in NP tissue of 12-month-old <i>Col2a1-Cre; Atg7</i> <sup><i>fl/fl</i></sup> mice compared to controls, suggesting <i>p21</i> <sup><i>CIP1</i></sup>-mediated cellular senescence resulted from NP-targeted <i>Atg7</i> knockout might contribute to the observed histological changes. The absence of overt IDD features from disrupting <i>Atg7</i>-mediated macroautophagy in NP tissue implicates other compensatory mechanisms, highlighting additional research needed to elucidate the complex biology of autophagy in regulating age-dependent IDD.