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

Abstract

<p>Biglycan, a pericellular small leucine-rich proteoglycan (SLRP), plays crucial roles 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, the role of Bgm1 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 nucleo-cytoplasmic transport. Induced IDD in mice showed elevated nuclear eIF6 expression and reduced Bgm1 in degenerating nucleus pulposus. Transcriptome analysis suggests Bgm1 regulates fatty acid metabolism and glycolysis in a TGF-beta-dependent manner, highlighting its potential role in metabolic control in spinal joint homeostasis.</p>