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Abstract
Cellular dysfunction induced by senescent nucleus pulposus (NP) cells is a key factor in the pathogenesis of intervertebral disc degeneration (IDD). Stathmin 1 (STMN1) has been proposed as a telomere-associated senescence marker implicated in senescence in many age-related diseases. Nevertheless, its role in NP cell senescence remains unclear. This study revealed that STMN1 was significantly upregulated in human degenerative and naturally aged rat NP tissue specimens. In vitro models demonstrated that STMN1 expression levels were elevated in replicative and TNF-α-induced NP senescence models. Lentiviral knockdown of STMN1 inhibited NP cell senescence, while overexpression promoted NP cell senescence, along with extracellular matrix (ECM) degradation. An in-depth mechanism indicated that insulin-like growth factor-binding protein 5 (IGFBP5), a downstream pro-senescence gene of STMN1, can induce NP cellular senescence and ECM degradation following its upregulation by STMN1. Furthermore, STMN1 knockdown reduced IGFBP5 expression and mitigated IDD development in a rat model of caudal discs puncture-induced IDD. Combined with the abovementioned results, we demonstrated for the first time that the STMN1–IGFBP5 axis can induce NP cell senescence and ECM degradation, thereby accelerating IDD development. This provides a robust foundation for the development of molecular-targeted therapies for IDD.
Highlights
According to statistics, about one-third of the world’s musculoskeletal disorders are caused by low back pain (LBP), and its disability rate is increasing year by year, gradually becoming the leading cause of disability in underdeveloped regions (Cieza et al 2021; Sharma and McAuley 2022)
Stathmin 1 (STMN1) expression in human degenerative nucleus pulposus (NP) tissues We investigated the potential correlation between the expression level of STMN1 and the development of human Intervertebral disc degeneration (IDD)
Immunohistochemical analysis showed that the expression of p16, p21, MMP3, and STMN1 increased, while the expression of Collagen II decreased in the high-grade IDD (HIDD) group (Fig. 1C and L–P)
Summary
About one-third of the world’s musculoskeletal disorders are caused by low back pain (LBP), and its disability rate is increasing year by year, gradually becoming the leading cause of disability in underdeveloped regions (Cieza et al 2021; Sharma and McAuley 2022). Its pathogenesis is related to various factors, including the production of senescent cells, abnormal mechanical stimuli, metabolic disorders, inflammatory responses, and oxidative stress (Silwal et al 2023; Francisco et al 2022; Wang et al 2023). An in-depth understanding of the molecular mechanisms underlying IDD pathogenesis will provide new therapeutic strategies. NP cell senescence and disturbances in ECM metabolism are often considered key components in the development of IDD (Xu et al 2023). Numerous studies have reported protective effects against IDD by inhibiting NP cell senescence and ECM degradation (Zhang et al 2022; Chen et al 2018). Studies on the mechanisms of NP cell senescence and ECM metabolism may help better understand the pathogenesis of IDD and identify new potential therapeutic targets
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