FSTL1 accelerates nucleus pulposus-derived mesenchymal stem cell apoptosis in intervertebral disc degeneration by activating TGF-β-mediated Smad2/3 phosphorylation

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 26, 2025

Intervertebral disc degeneration (IVDD) is the leading cause of low back pain, and repair using nucleus pulposus-derived mesenchymal stem cells (NP-MSCs) represents a promising therapeutic approach. However, both endogenous transplanted NP-MSCs demonstrate limited proliferative capacity, increased apoptosis, reduced resilience to harsh microenvironment within degenerative intervertebral (IVD). RNA sequencing (RNA-seq) was utilized identify genes associated mechanisms that mediate responses acidic conditions. Western blotting, qPCR, immunofluorescence were used evaluate follistatin-like 1 (FSTL1) expression in NP-MSCs. Apoptosis extracellular matrix (ECM) anabolism assessed via flow cytometry, TUNEL staining while TGF-β/Smad2/3 pathway analyzed blotting immunofluorescence. FSTL1 knockdown with small interfering (siRNA) performed determine its role apoptosis ECM regulation. The siRNA pretreatment puncture-induced rat IVDD model MRI histological staining. Using RNA-seq, we identified as primary acid-responsive gene We further observed elevated isolated from IVDs humans rats compared normal IVDs. Acidic conditions upregulated pH-dependent manner. Notably, recombinant shown enhance cellular disrupt metabolism. Conversely, silencing NP-MSC improved anabolism. Importantly, TGF-β inhibition partially reversed pro-apoptotic catabolism effects FSTL1. In IVDD, significantly suppressed progression. This study provides novel insights into mechanistic acid-induced contribution progression IVDD. These findings offer valuable perspectives for developing targeted strategies mitigate

Language: Английский

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Single-nuclei RNA Sequencing Reveals Distinct Transcriptomic Signatures of Rat Dorsal Root Ganglia in a Chronic Discogenic Low Back Pain Model

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

Chronic low back pain (LBP), often correlated with intervertebral disc degeneration, is a leading source of disability worldwide yet remains poorly understood. Current treatments fail to provide sustained relief, highlighting the need better understand mechanisms driving discogenic LBP. During extracellular matrix degrades, allowing nociceptive nerve fibers innervate previously aneural regions. Persistent mechanical and inflammatory stimulation nociceptors can induce plastic changes within dorsal root ganglia (DRG) neurons, characterized by altered gene expression, enhanced excitability, lowered activation thresholds. Although these transcriptional have been described in other states, including osteoarthritis, they remain underexplored To address this gap, study represents first application comprehensive single-nuclei RNA sequencing DRG neurons rat model chronic Eighteen distinct subpopulations were identified mapped existing mouse cross-species atlases revealing strong similarities neuronal populations mouse. Differential expression analysis revealed increased pain-associated genes, Scn9a Piezo2 , neuroinflammatory mediators such as Fstl1 Ngfr LBP animals. Axial hypersensitivity, measured using grip strength, significantly Scn9a, Fstl1, Ngfr, which suggests their role maintaining axial hypersensitivity model. These findings establish relationship between transcriptomic model, identifying potential molecular targets for non-opioid advancing understanding mechanisms.

Language: Английский

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Role of oxidative stress in intervertebral disc degeneration: mechanisms, pathogenesis, and therapeutic strategies

Molecular Biology Reports, Journal Year: 2025, Volume and Issue: 52(1)

Published: May 2, 2025

Language: Английский

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Involvement of Matricellular Proteins in Cellular Senescence: Potential Therapeutic Targets for Age-Related Diseases

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(12), P. 6591 - 6591

Published: June 15, 2024

Senescence is a physiological and pathological cellular program triggered by various types of stress. Senescent cells exhibit multiple characteristic changes. Among them, the flattened enlarged morphology exhibited in senescent observed regardless stimuli causing senescence. Several studies have provided important insights into pro-adhesive properties senescence, suggesting that cell adhesion to extracellular matrix (ECM), which involved morphological changes, may play pivotal roles Matricellular proteins, group structurally unrelated ECM molecules are secreted environment, unique ability control binding receptors, including integrins. Recent reports certified matricellular proteins closely Through this biological function, thought pathogenesis age-related diseases, fibrosis, osteoarthritis, intervertebral disc degeneration, atherosclerosis, cancer. This review outlines recent on role inducing We highlight integrin-mediated signaling senescence provide new therapeutic options for diseases targeting

Language: Английский

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FSTL1 and TLR4 interact with PEDV structural proteins to promote virus adsorption to host cells

Journal of Virology, Journal Year: 2024, Volume and Issue: 99(1)

Published: Dec. 13, 2024

Infection with porcine epidemic diarrhea virus (PEDV) results in enormous economic damage to the global swine industry. PEDV starts its life cycle by binding receptors of host cells and adsorbing onto cellular surfaces. However, it is still unknown how adsorbs surface mechanism beneath interplay cell transmembrane protein proteins. FSTL1, which a secreted glycoprotein, participates diverse pathological physiological processes, including immune modulation proliferation differentiation. The protein, TLR4, serves as pattern recognition receptor recognizing broad spectrum pathogens, exerts crucial effect on system. In this study, we identified that FSTL1 promoted infection. Further studies demonstrated interactive relationship between structural proteins (N S2). addition, also confirmed TLR4 interacted N, S1, S2 surface. Moreover, interaction induced viral adsorption cells. This study offers explicit evidence act mediators for interacting N/S proteins.IMPORTANCEAs highly infectious (PEDV)-induced intestinal condition swine, (PED) 100% death rate among suckling piglets poses serious burden farming. Therefore, essential investigate infection, replication, proliferation. Virus begins remains unclear revealed N proteins, while (N, thoroughly methodically was engaged internalization attachment processes promoting N\S

Language: Английский

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The regulatory mechanism of cyclic GMP-AMP synthase on inflammatory senescence of nucleus pulposus cell

Journal of Orthopaedic Surgery and Research, Journal Year: 2024, Volume and Issue: 19(1)

Published: July 22, 2024

Abstract Background Cellular senescence features irreversible growth arrest and secretion of multiple proinflammatory cytokines. Cyclic GMP-AMP synthase (cGAS) detects DNA damage activates the DNA-sensing pathway, resulting in upregulation inflammatory genes induction cellular senescence. This study aimed to investigate effect cGAS regulating nucleus pulposus (NP) cells under microenvironment. Methods The expression was evaluated by immunohistochemical staining rat intervertebral disc (IVD) degeneration model induced annulus stabbing. NP were harvested from lumbar IVD cultured with 10ng/ml IL-1β for 48 h induce premature silenced specific siRNA IL-1β. senescence-associated beta-galactosidase (SA-β-gal) flow cytometry. secretory phenotype including IL-6, IL-8, TNF-a ELISA western blotting. Results detected cytoplasm significantly increased degenerated IVD. Culturing attenuation G1-S phase transition. In senescent cGAS, p53, p16, NF-kB, TNF-α while aggrecan collagen type II reduced than normal cells. culturing Conclusion promoting phenotypes. Targeting may alleviate reducing cell

Language: Английский

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Nordihydroguaiaretic acid suppresses ferroptosis and mitigates intervertebral disc degeneration through the NRF2/GPX4 axis

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 143, P. 113590 - 113590

Published: Nov. 15, 2024

Language: Английский

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COULD PHARMACOLOGICAL TARGETING MITOPHAGIC OR LYSOPHAGIC SIGNALING PATHWAYS BE A NEW HOPE IN THE TREATMENT OF INTERVERTEBRAL DISC DEGENERATION?

Journal of Turkish Spinal Surgery, Journal Year: 2024, Volume and Issue: 35(2), P. 85 - 91

Published: April 1, 2024

Language: Английский

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