Oxidative stress induces intervertebral ECM remodelling, elevated tissue stiffness and idiopathic-like scoliosis

Oxidative stress induces intervertebral ECM remodelling, elevated tissue stiffness and idiopathic-like scoliosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Oxidative stress induces intervertebral ECM remodelling, elevated tissue stiffness and idiopathic-like scoliosis Brian Ciruna, Patrick Pumputis, Ran Xu, Josh Gopaul, Arash Panahifar, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4978808/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Sep, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Adolescent idiopathic scoliosis (AIS) is the most prevalent paediatric spine disorder, developing in the absence of obvious congenital or physiological defects. Patient genetic sequencing and mouse functional studies have demonstrated association of musculoskeletal collagen variants and cartilaginous extracellular matrix (ECM) defects in a subset of cases. However, the underlying biological causes of AIS are poorly understood, thus treatment options remain limited to physical bracing or invasive corrective surgery. Here we interrogate the biological causes of scoliosis in zebrafish preclinical models of AIS. We demonstrate that neuroinflammation-associated reduction-oxidation (redox) imbalance induces cell stress and collagen remodelling defects within intervertebral segments of the developing spine. Mutant spines are consequently stiffer, as measured by shear wave elastography, and exhibit deformations of intervertebral structures. Remarkably, both elevated spine stiffness and intervertebral ECM phenotypes are detectable prior to scoliosis onset in zebrafish models, suggesting a causal relationship, and can be suppressed by antioxidant treatment. Together, our studies implicate oxidative stress-induced intervertebral deformations in the pathogenesis of AIS and identify elevated spine stiffness and redox imbalance as plausible first-in-kind prognostic biomarkers and therapeutic targets. Biological sciences/Developmental biology/Disease model Biological sciences/Developmental biology/Cartilage development Health sciences/Medical research/Experimental models of disease Health sciences/Biomarkers/Predictive markers Health sciences/Medical research/Preclinical research Full Text Additional Declarations There is NO Competing Interest. Supplementary Files MovieS1WTtransverse.mov Supplementary Video 1. Wildtype microCT images, transverse plane. MovieS2WTcoronal.mov Supplementary Video 2. Wildtype microCT images, coronal plane. MovieS3sspotransverse.mov Supplementary Video 3. sspo dmh4/+ microCT images, transverse plane. MovieS4sspocoronal.mov Supplementary Video 4. sspo dmh4/+ microCT images, coronal plane. MovieS5WTIVL2coronal.mov Supplementary Video 5. Wildtype zebrafish exhibit stable IVL structures (example 2). MovieS6sspoIVL2coronal.mov Supplementary Video 6. Scoliotic zebrafish exhibit IVL deformations (example 2). MovieS7sspoIVL3coronal.mov Supplementary Video 7. Scoliotic zebrafish exhibit IVL deformations (example 3). Cite Share Download PDF Status: Published Journal Publication published 30 Sep, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4978808","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":350473547,"identity":"cf2fc3e2-1dd9-4986-9503-1195e77ee74d","order_by":0,"name":"Brian 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Patient genetic sequencing and mouse functional studies have demonstrated association of musculoskeletal collagen variants and cartilaginous extracellular matrix (ECM) defects in a subset of cases. However, the underlying biological causes of AIS are poorly understood, thus treatment options remain limited to physical bracing or invasive corrective surgery. Here we interrogate the biological causes of scoliosis in zebrafish preclinical models of AIS. We demonstrate that neuroinflammation-associated reduction-oxidation (redox) imbalance induces cell stress and collagen remodelling defects within intervertebral segments of the developing spine. Mutant spines are consequently stiffer, as measured by shear wave elastography, and exhibit deformations of intervertebral structures. Remarkably, both elevated spine stiffness and intervertebral ECM phenotypes are detectable prior to scoliosis onset in zebrafish models, suggesting a causal relationship, and can be suppressed by antioxidant treatment. 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