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

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.