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Autophagy, negatively regulated by the phosphatidylinositol 3\u2010kinase (PI3K)\/Akt\/mammalian target of rapamycin (mTOR) signaling pathway, prevents metabolic and degenerative diseases by removing and recycling damaged cellular components. Despite growing evidence that autophagy occurs in the intervertebral disc, the regulation of disc cellular autophagy is still poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Annulus fibrosus (rAF) cell cultures derived from healthy female rabbit discs were used to test the effect of autophagy inhibition or activation on disc cell fate and matrix homeostasis. Specifically, different chemical inhibitors including rapamycin, 3\u2010methyladenine, MK\u20102206, and PP242 were used to modulate activities of different proteins in the PI3K\/Akt\/mTOR signaling pathway to assess IL\u20101\u03b2\u2010induced cellular senescence, apoptosis, and matrix homeostasis in rAF cells grown under nutrient\u2010poor culture condition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Rapamycin, an inhibitor of mTOR complex 1 (mTORC1), reduced the phosphorylation of mTOR and its effector p70\/S6K in rAF cell cultures. Rapamycin also induced autophagic flux as measured by increased expression of key autophagy markers, including LC3 puncta number, LC3\u2010II expression, and cytoplasmic HMGB1 intensity and decreased p62\/SQSTM1 expression. As expected, IL\u20101\u03b2 stimulation promoted rAF cellular senescence, apoptosis, and matrix homeostatic imbalance with enhanced aggrecanolysis and MMP\u20103 and MMP\u201013 expression. Rapamycin treatment effectively mitigated IL\u20101\u03b2\u2010mediated inflammatory stress changes, but these alleviating effects of rapamycin were abrogated by chemical inhibition of Akt and mTOR complex 2 (mTORC2).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings suggest that rapamycin blunts adverse effects of inflammation on disc cells by inhibiting mTORC1 to induce autophagy through the PI3K\/Akt\/mTOR pathway that is dependent on Akt and mTORC2 activities. Hence, our findings identify autophagy, rapamycin, and PI3K\/Akt\/mTOR signaling as potential therapeutic targets for IDD treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jsp2.1303","type":"journal-article","created":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T01:00:07Z","timestamp":1704243607000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Rapamycin mitigates inflammation\u2010mediated disc matrix homeostatic imbalance by inhibiting\n                    <scp>mTORC1<\/scp>\n                    and inducing autophagy through Akt activation"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3007-361X","authenticated-orcid":false,"given":"Takashi","family":"Yurube","sequence":"first","affiliation":[{"name":"Ferguson Laboratory for Orthopaedic and Spine Research, Department of Orthopaedic Surgery University of Pittsburgh Medical Cancer, University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Orthopaedic Surgery Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Buchser","sequence":"additional","affiliation":[{"name":"Damage Associated Molecular Pattern Molecule Laboratory, Department of Surgery, Hillman Cancer Center University of Pittsburgh Cancer Institute, University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Ferguson Laboratory for Orthopaedic and Spine Research, Department of Orthopaedic Surgery University of Pittsburgh Medical Cancer, University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Orthopaedic Surgery Kobe University Graduate School of Medicine  Kobe 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Orthopaedic and Spine Research, Department of Orthopaedic Surgery University of Pittsburgh Medical Cancer, University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Orthopedics, Brigham and Women's Hospital, School of Medicine Harvard University  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwendolyn A.","family":"Sowa","sequence":"additional","affiliation":[{"name":"Ferguson Laboratory for Orthopaedic and Spine Research, Department of Orthopaedic Surgery University of Pittsburgh Medical Cancer, University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Physical Medicine and Rehabilitation University of Pittsburgh Medical Cancer, University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nam V.","family":"Vo","sequence":"additional","affiliation":[{"name":"Ferguson Laboratory for Orthopaedic and Spine Research, Department of Orthopaedic 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