miR-204-5p Mitigates Disc Degeneration via SKI-Mediated Modulation of Apoptotic Signaling and Matrix Remodeling in Nucleus Pulposus

Dysregulation of nucleus pulposus cells (NPCs) is a critical contributor to intervertebral disc degeneration (IDD). One characteristic of degenerated discs is the increased apoptosis of NPCs and the substantial degradation of the extracellular matrix (ECM). This study identified significantly reduced miR-204-5p levels in IDD tissues. Using lipopolysaccharide (LPS)-treated rat NPCs, miR-204-5p overexpression was found to suppress apoptosis, reduce ECM degradation, and enhance ECM synthesis. Mechanistically, SKI was identified as a direct target of miR-204-5p, with its expression markedly elevated in IDD tissues. Functional assays revealed that modulating SKI expression (overexpression or knockdown) influenced LPS-induced apoptosis, ECM synthesis, and degradation in NPCs. Notably, SKI overexpression exacerbated LPS-induced damage and counteracted the protective effects of miR-204-5p. Importantly, intradiscal delivery of agomiR-204-5p effectively alleviated IDD progression in vivo. Overall, these results emphasize the pivotal role of miR-204-5p in mitigating IDD by targeting SKI, thereby regulating NPC apoptosis and ECM homeostasis. The miR-204-5p/SKI axis thus presents a promising therapeutic avenue for treating IDD.