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FSTL1 Accelerates Nucleus Pulposus Cell Senescence and Intervertebral Disc Degeneration Through TLR4/NF-κB Pathway

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Abstract

Intervertebral disc degeneration (IVDD) is a major contributor to low back pain (LBP), and inflammatory factors play crucial roles in its pathogenesis. Follistatin-like 1 (FSTL1) has been reported to induce an inflammatory response in chondrocytes, microglia and preadipocytes, but its role in the pathogenesis of nucleus pulposus cell (NPC) degeneration remains unclear. In this study, we mainly utilized an acidosis-induced NPC degeneration model and a rabbit puncture IVDD model to investigate the role of FSTL1 in IVDD both in vitro and in vivo. We confirmed that FSTL1 expression significantly increased in nucleus pulposus (NP) tissues from IVDD patients and rabbit puncture IVDD models. The expression levels of FSTL1 were significantly increased in all three models of NPC degeneration under harsh microenvironments. In addition, recombinant human FSTL1 (rh-FSTL1) was found to upregulate the expression of p16 and p21, increase the number of senescence-associated β-galactosidase (SA-β-gal)-positive cells, induce senescence-related secretory phenotypes (SASP), and downregulate extracellular matrix (ECM) protein expressions, leading to an imbalance in ECM metabolism destructions. Conversely, silencing of FSTL1 by small interfering RNA (siRNA) ameliorated senescence of NPCs associated with inflammation in IVDD. Furthermore, Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway plays a crucial role in regulating NPC senescence through FSTL1 regulation. Inhibition of TLR4 expression partly reversed the effects of rh-FSTL1 on NPC senescence-associated inflammation. Finally, rabbit IVDD model experiments demonstrated that the specific FSTL1 siRNA markedly repressed the development of IVDD. These findings may offer a therapeutic approach for mitigating inflammation-induced senescence associated with IVDD.

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Funding

This study was supported by the National Natural Science Foundation of China (81772408).

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Authors and Affiliations

  1. Department of Orthopedics and Spine Surgery, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China

    Xu Yan, Jing-Yu Ding, Ren-Jie Zhang, Hua-Qing Zhang, Liang Kang, Chong-Yu Jia & Cai-Liang Shen

  2. Laboratory of Spinal and Spinal Cord Injury Regeneration and Repair, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China

    Xu Yan, Jing-Yu Ding, Ren-Jie Zhang, Hua-Qing Zhang, Liang Kang, Chong-Yu Jia & Cai-Liang Shen

  3. School of Life Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China

    Xiao-Ying Liu

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  1. Xu Yan
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Contributions

XY and JYD carried out the conception and design of the research. JYD and RJZ participated in the acquisition of data. HQZ, LK, and CYJ carried out the analysis and interpretation of data. XY and JYD performed the statistical analysis. XY and RJZ drafted the manuscript, and XYL and CLS participated in revision of manuscript for important intellectual content. All authors read and approved the final manuscript. XY, JYD, and RJZ contributed equally to this work. All authors reviewed the manuscript.

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Correspondence to Xiao-Ying Liu or Cai-Liang Shen.

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Yan, X., Ding, JY., Zhang, RJ. et al. FSTL1 Accelerates Nucleus Pulposus Cell Senescence and Intervertebral Disc Degeneration Through TLR4/NF-κB Pathway. Inflammation (2024). https://doi.org/10.1007/s10753-024-01972-0

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