{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T01:23:10Z","timestamp":1787448190536,"version":"build-2736575974"},"posted":{"date-parts":[[2023,8,8]]},"group-title":"Bioengineering","reference-count":47,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,8,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Low back pain (LBP) is the leading cause of global disability and is thought to be driven primarily by intervertebral disc (IVD) degeneration (DD). Persistent upregulation of catabolic enzymes and inflammatory mediators have been associated with severe cases of DD. Nuclear factor kappa B (NF-\u03baB) is a master transcription regulator of immune responses and is over expressed during inflammatory-driven musculoskeletal diseases, including DD. However, its role in triggering DD is unknown. Therefore, this study investigated the effect of NF-\u03baB pathway over-activation on IVD integrity and DD pathology.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Using skeletally mature mouse model, we genetically targeted IVD cells for canonical NF-\u03baB pathway activation via expression of a constitutively active form of inhibitor of \u03baB kinase B (IKK\u03b2), and assessed changes in IVD cellularity, structural integrity including histology, disc height, and extracellular matrix (ECM) biochemistry, biomechanics, expression of inflammatory, catabolic, and neurotropic mediators, and changes in macrophage subsets, longitudinally up to 6-months post activation.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Prolonged NF-\u03baB activation led to severe structural degeneration, with a loss of glycosaminoglycan (GAG) content and complete loss of nucleus pulposus (NP) cellularity. Structural and compositional changes decreased IVD height and compressive mechanical properties with prolonged NF-\u03baB activation. These alterations were accompanied by increases in gene expression of inflammatory molecules (\n                    <jats:italic>Il1b, Il6, Nos2<\/jats:italic>\n                    ), chemokines (\n                    <jats:italic>Mcp1<\/jats:italic>\n                    ,\n                    <jats:italic>Mif<\/jats:italic>\n                    ), catabolic enzymes (\n                    <jats:italic>Mmp3, Mmp9, Adamts4<\/jats:italic>\n                    ), and neurotrophic factors (\n                    <jats:italic>Bdnf<\/jats:italic>\n                    ,\n                    <jats:italic>Ngf<\/jats:italic>\n                    ) within IVD tissue. Increased recruitment of activated\n                    <jats:italic>F4\/80<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    macrophages exhibited a greater abundance of pro-inflammatory (CD38\n                    <jats:sup>+<\/jats:sup>\n                    ) over inflammatory-resolving (CD206\n                    <jats:sup>+<\/jats:sup>\n                    ) macrophage subsets in the IVD, with temporal changes in the relative abundance of macrophage subsets over time, providing evidence for temporal regulation of macrophage polarization in DD\n                    <jats:italic>in vivo,<\/jats:italic>\n                    where macrophages participate in resolving the inflammatory cascade but promote fibrotic transformation of the IVD matrix. We further show that NF-\u03baB driven secretory factors from IVD cells increase macrophage migration and inflammatory activation, and that the secretome of inflammatory-resolving macrophages mitigates effects of NF-\u03baB overactivation.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Overall the observed results suggest prolonged NF-\u03baB activation can induce severe DD, acting through increases in inflammatory cytokines, chemotactic proteins, catabolic enzymes, and the recruitment and inflammatory activation of a macrophage cell populations, that can be mitigated with inflammatory-resolving macrophage secretome.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.08.07.552274","type":"posted-content","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T13:30:13Z","timestamp":1691501413000},"source":"Crossref","is-referenced-by-count":3,"title":["Nuclear Factor Kappa B Over-Activation in the Intervertebral Disc Leads to Macrophage Recruitment and Severe Disc Degeneration"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8504-7980","authenticated-orcid":false,"given":"Kevin G.","family":"Burt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8339-7768","authenticated-orcid":false,"given":"Min Kyu M.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6173-8004","authenticated-orcid":false,"given":"Dan C.","family":"Viola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2131-5178","authenticated-orcid":false,"given":"Adam C.","family":"Abraham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0478-6042","authenticated-orcid":false,"given":"Nadeen O.","family":"Chahine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"6","key":"2023081105050461000_2023.08.07.552274v1.1","first-page":"591","volume":"310","year":"2013","journal-title":"The state of US health, 1990-2010: burden of diseases, injuries, and risk factors"},{"key":"2023081105050461000_2023.08.07.552274v1.2","doi-asserted-by":"publisher","DOI":"10.2106\/JBJS.E.01273"},{"key":"2023081105050461000_2023.08.07.552274v1.3","doi-asserted-by":"crossref","unstructured":"Luoma, K. , et al., Low back pain in relation to lumbar disc degeneration. 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