Targeted modulation of phosphate and lipid metabolism reduces ligament mineralization in col9a1b knockout models

Intervertebral disc degeneration (IVDD) is a major global cause of chronic back pain and disability in the aging population, characterized by disc matrix breakdown, ligament mineralization, and pain. Effective pharmacological treatments for IVDD are currently unavailable. We used col9a1b mutant zebrafish to elucidate the genetic and molecular mechanisms of disc disease, with a focus on ectopic mineralization. We found that col9a1b mutants exhibit ectopic intervertebral ligament mineralization, vertebral fusions, and disc degeneration, mirroring human IVDD. Histological, electron microscopy, and molecular analyses revealed that structural disorganization of the notochord epithelium underpins these vertebral fusions. Transcriptomic profiling implicated dysregulation of lipid metabolism and mTOR signalling in ligament biomineralization and vertebral column degeneration in the mutants. Pharmacological interventions targeting phosphate buffering, retinoic acid, lipid metabolism, and mTOR signalling successfully reduced vertebral fusion events. Notably, bisphosphonates and calorie restriction demonstrated superior efficacy in reducing ligament mineralization. Our findings establish col9a1b zebrafish mutants as a valuable model for investigating ligament mineralization and vertebral column degeneration, while identifying promising therapeutic targets, including phosphate and lipid metabolism pathways.