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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\u2010established as a major driver of many age\u2010related diseases, autophagy dysregulation or deficiency has yet been confirmed to cause IDD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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 (\n                      <jats:italic>Col2a1\u2010Cre<\/jats:italic>\n                      ;\n                      <jats:italic>Atg7<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>fl\/fl<\/jats:italic>\n                      <\/jats:sup>\n                      ) mice were successfully generated to inhibit autophagy primarily in NP tissues.\n                      <jats:italic>Col2a1\u2010Cre<\/jats:italic>\n                      ;\n                      <jats:italic>Atg7<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>fl\/fl<\/jats:italic>\n                      <\/jats:sup>\n                      mouse intervertebral discs (IVDs) were evaluated for biomarkers for apoptosis and cellular senescence, aggrecan content, and histological changes up to 12\u2009months of age.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Here, we demonstrated inhibition of autophagy by bafilomycin produced IDD features in the rat NP cells, including increased apoptosis and cellular senescence (\n                      <jats:italic>p21<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>CIP1<\/jats:italic>\n                      <\/jats:sup>\n                      ) and decreased expression of disc matrix genes\n                      <jats:italic>Col2a1<\/jats:italic>\n                      and\n                      <jats:italic>Acan<\/jats:italic>\n                      . H&amp;E histologic staining showed significant but modest degenerative changes in NP tissue of\n                      <jats:italic>Col2a1\u2010Cre; Atg7<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>fl\/fl<\/jats:italic>\n                      <\/jats:sup>\n                      mice compared to controls at 6 and 12\u2009months of age. Intriguingly, 12\u2010month\u2010old\n                      <jats:italic>Col2a1\u2010Cre; Atg7<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>fl\/fl<\/jats:italic>\n                      <\/jats:sup>\n                      mice did not display increased loss of NP proteoglycan. Moreover, markers of apoptosis (cleaved caspase\u20103, TUNEL), and cellular senescence (p53,\n                      <jats:italic>p16<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>INK4a<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>,<\/jats:italic>\n                      IL\u20101\u03b2, TNF\u2010\u03b1) were not affected in 12\u2010month\u2010old\n                      <jats:italic>Col2a1\u2010Cre; Atg7<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>fl\/fl<\/jats:italic>\n                      <\/jats:sup>\n                      mice compared to controls. However,\n                      <jats:italic>p21<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>CIP1<\/jats:italic>\n                      <\/jats:sup>\n                      and\n                      <jats:italic>Mmp13<\/jats:italic>\n                      gene expression were upregulated in NP tissue of 12\u2010month\u2010old\n                      <jats:italic>Col2a1\u2010Cre; Atg7<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>fl\/fl<\/jats:italic>\n                      <\/jats:sup>\n                      mice compared to controls, suggesting\n                      <jats:italic>p21<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>CIP1<\/jats:italic>\n                      <\/jats:sup>\n                      \u2010mediated cellular senescence resulted from NP\u2010targeted\n                      <jats:italic>Atg7<\/jats:italic>\n                      knockout might contribute to the observed histological changes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The absence of overt IDD features from disrupting\n                      <jats:italic>Atg7<\/jats:italic>\n                      \u2010mediated macroautophagy in NP tissue implicates other compensatory mechanisms, highlighting additional research needed to elucidate the complex biology of autophagy in regulating age\u2010dependent IDD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jsp2.1286","type":"journal-article","created":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T21:50:41Z","timestamp":1694641841000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Impact of autophagy inhibition on intervertebral disc cells and 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