Oxidative stress-induced intervertebral disc remodelling and elevated stiffness drive idiopathic scoliosis in preclinical models

Adolescent idiopathic scoliosis (AIS) is the most prevalent pediatric spine disorder, developing in the absence of obvious physiological defects. Genome sequencing and functional studies have demonstrated association of musculoskeletal collagen variants and cartilaginous extracellular matrix (ECM) defects in a subset of patients. However, the underlying biological causes of AIS remain poorly understood, limiting treatment options. Using multiple zebrafish AIS models, we demonstrate that reduction-oxidation (redox) imbalances induce cell stress and collagen remodelling 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, elevated stiffness and intervertebral ECM phenotypes are detectable prior to scoliosis onset, suggesting a causal relationship, and can be suppressed by antioxidant treatment. Together, our preclinical 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.