Biglycan fragment modulates TGF-β activity in intervertebral disc via an eIF6-coupled intracellular path

Biglycan, a pericellular small leucine-rich proteoglycan, is crucial in skeletal development and regeneration. Intervertebral disc degeneration (IDD) contributes to back pain and disability. Previous studies have shown that biglycan promotes hypoxic survival of disc progenitor cells, while its depletion accelerates IDD. An association of pathological tissue remodeling with a biglycan fragment ³⁴⁴YWEVQPATFR, termed Bgm1, has been reported, however its role is yet to be defined. Using a custom antibody, we detected Bgm1 in human and mouse nucleus pulposus, with prominent intracellular expression in notochordal cells. Proteomic analysis revealed that Bgm1 interacts with eukaryotic translation initiation factor 6 (eIF6), a key player in ribosome biogenesis. Bgm1 dysregulates eIF6 localization in notochordal cells, affecting nucleocytoplasmic transport. Induced IDD in mice showed elevated nuclear eIF6 expression and reduced Bgm1 in degenerating nucleus pulposus. Transcriptome analysis suggests that Bgm1 regulates fatty acid metabolism and glycolysis in a transforming growth factor-β-dependent manner, highlighting its potential role in metabolic control in spinal joint homeostasis.