Targeted modulation of phosphate and lipid metabolism reduces ligament mineralization in col9a1b deficient zebrafish

Abstract Intervertebral disc degeneration (IVDD) is a major global cause of back pain and disability in the elderly, characterized by matrix breakdown, ligament mineralization, and pain. Effective pharmacological treatments for IVDD are currently unavailable. We used col9a1b −/− zebrafish to elucidate the genetic and molecular mechanisms of IVDD, with a focus on ectopic mineralization. col9a1b −/− exhibit ectopic intervertebral ligament mineralization, vertebral fusions, and disc degeneration, resembling human IVDD. Histological, electron microscopy, and molecular analyses revealed that structural disorganization of the notochord epithelium underpins vertebral fusions. Transcriptomic profiling implicated dysregulation of lipid metabolism and mTOR signalling in ligament biomineralization and degeneration in col9a1b−/− . Pharmacological interventions targeting phosphate, retinoic acid, lipid metabolism, and mTOR signalling successfully reduced vertebral fusions. Notably, bisphosphonates and calorie restriction demonstrated efficacy in reducing ligament mineralization. Our findings establish a valuable model for investigating ligament mineralization and IVDD, while suggesting phosphate and lipid metabolism pathways as therapeutic routes.