Targeting Piezo1 channel to alleviate intervertebral disc degeneration

Journal of Orthopaedic Translation, Journal Year: 2025, Volume and Issue: 51, P. 145 - 158

Published: March 1, 2025

Low back pain impacts over 600 million people worldwide, predominantly due to intervertebral disc degeneration. This study focuses on the role of Piezo1, a crucial mechanosensitive ion channel protein, in pathology and potential treatment To investigate effects disc-specific Piezo1 deletion, we generated Aggrecan CreERT2 ; fl/fl mice examined both lumbar spine instability (LSI)- aging-induced Additionally, effect pharmacological inhibition was evaluated using GsMTx4, potent antagonist, an ex vivo model stimulated with IL-1β induce Assessments included histological examinations, immunofluorescence, western blot analyses thoroughly characterize alterations discs. Elevated expression detected nucleus pulposus (NP) discs advanced degeneration aged human patients. Inducible deletion aggrecan-expressing cells significantly reduced degeneration, decreased extracellular matrix (ECM) degradation, lowered apoptosis NP cells, observed those undergoing LSI surgery. Excessive compression loading (CL) upregulated expression, induced ECM disruption, increased whereas GsMTx4 effectively mitigated these pathological changes. Furthermore, cultured mouse discs, alleviated IL-1β-induced degenerative damages, restored anabolism, apoptosis. The findings suggest that plays critical development highlight its as therapeutic target. Inhibiting could offer novel strategy for treating or preventing this disease. research highlights involvement emphasizes targeting delay reverse condition.

Language: Английский

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The Sanbi Decoction alleviates intervertebral disc degeneration in rats through intestinal flora and serum metabolic homeostasis modulation

Phytomedicine, Journal Year: 2024, Volume and Issue: 127, P. 155480 - 155480

Published: Feb. 24, 2024

Language: Английский

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Altered Metabolism and Inflammation Driven by Post-translational Modifications in Intervertebral Disc Degeneration

Research, Journal Year: 2024, Volume and Issue: 7

Published: Jan. 1, 2024

Intervertebral disc degeneration (IVDD) is a prevalent cause of low back pain and leading contributor to disability. IVDD progression involves pathological shifts marked by low-grade inflammation, extracellular matrix remodeling, metabolic disruptions characterized heightened glycolytic pathways, mitochondrial dysfunction, cellular senescence. Extensive posttranslational modifications proteins within nucleus pulposus cells chondrocytes play crucial roles in reshaping the intervertebral phenotype orchestrating metabolism inflammation diverse contexts. This review focuses on pivotal phosphorylation, ubiquitination, acetylation, glycosylation, methylation, lactylation pathogenesis. It integrates latest insights into various modification-mediated inflammatory signaling networks, laying groundwork for targeted proteomics metabolomics treatment. The discussion also highlights unexplored territories, emphasizing need future research, particularly understanding role health, an area currently shrouded mystery.

Language: Английский

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Effects of the PI3K/Akt/HO-1 pathway on autophagy in a sepsis-induced acute lung injury mouse model

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 124, P. 111063 - 111063

Published: Oct. 17, 2023

Sepsis-induced lung injury is an acute hypoxic respiratory insufficiency caused by systemic infectious factors that results in alveolar epithelial cell and capillary endothelial injury, diffuse pulmonary interstitial edema, edema. Heme oxygenase (HO)-1 usually associated with inflammation has anti-inflammatory effects. Autophagy a degradation pathway eliminates cellular metabolic waste plays important protective role during stress. The phosphatidylinositol 3-kinase/ protein kinase B (PI3K/Akt) signaling key mediating responses to inflammatory reactions. Therefore, we hypothesized HO-1 autophagy regulated the PI3K/Akt mice sepsis-induced injury. was induced using cecal ligation puncture (CLP). Hemin or Sn-protoporphyrin IX (SnPP) administered via intraperitoneal injection before surgery. Survival rates were observed days 1-7 after surgery; histology discerned 24 h pro-inflammatory plasma tissue measured enzyme-linked immunosorbent assay (ELISA); HO-1, Beclin-1, microtubule-associated 1 light chain 3B (LC3B)-II, p62 lysosome membrane (LAMP)2 expression levels LC3B-II immunofluorescence autophagosomes detected electron microscopy Furthermore, when PI3K inhibitors LY294002, activators Recilisib hemin surgery, Akt, p-Akt, LC3-II post-surgery. We found overexpression increased survival rate inhibited attenuated of proinflammatory cytokines (TNF-α, IL-1β) cytokine (IL-10, HO-1) overexpression. Moreover, also LAMP2 expression; decreased significantly autophagosome formation. for HO-1-downregulated contrasted those mentioned above. LY294002 p-Akt/Akt, reversed inhibitory effect LY294002. involved mediation autophagy, which may be mice.

Language: Английский

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Rescuing ACE2‐Deficiency‐Mediated Nucleus Pulposus Senescence and Intervertebral Disc Degeneration by a Nanotopology‐Enhanced RNAi System

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Abstract Nucleus pulposus cell (NPC) senescence contributes to intervertebral disc degeneration (IVDD). However, the underlying molecular mechanisms are not fully understood. In this study, it is demonstrated that angiotensin‐converting enzyme 2 (ACE2) counteracted aging of NPCs and IVDD at cellular physiological levels. The expression ACE2 correlates negatively with degree NPC IVDD. Using both loss‐ gain‐of‐function mouse models, revealed deficiency increased exacerbated injury‐ or instability‐induced IVDD, whereas overexpression these detrimental effects. Mechanistically, integrated analysis single‐cell bulk transcriptomics shows results in activation TGFβ2/Smads signaling pathway transcription Serpine1, ultimately triggering A nanomedical delivery system (virus‐like nanovectors, VNs) composed nanovectors a virus‐like surface topology small interfering RNA targeting Serpine1 (VN‐siSer) developed. With nanotopology‐enhanced transfection efficiency, RNA‐interfering treatment by VN‐siSer effectively alleviated animal Overall, data reveal pathogenesis propose distinct paradigm precise senescence‐blockade RNAi for treatment.

Language: Английский

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Expression of MMP1, MMP3, and TIMP1 in intervertebral discs under simulated overload and microgravity conditions

Journal of Orthopaedic Surgery and Research, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 20, 2025

Language: Английский

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Intervertebral Disc Degeneration Mediates the Causal Effect of Genetically Predicted Diffuse Idiopathic Skeletal Hyperostosis on Spinal Stenosis: Evidence From a Mendelian Randomization Study

JOR Spine, Journal Year: 2025, Volume and Issue: 8(1)

Published: Jan. 20, 2025

ABSTRACT Background Previous studies have noted an association between diffuse idiopathic skeletal hyperostosis (DISH) and spinal stenosis (SS), although causation is unclear. This study used Mendelian randomization (MR) to investigate the causal relationship two. Methods We utilized large GWAS datasets on DISH SS perform a two‐sample, bidirectional MR analysis, also quantifying mediating role of intervertebral disc degeneration (IDD). The inverse variance weighting (IVW) method was primary approach estimate effect size. To ensure reliability results, we conducted heterogeneity tests, horizontal pleiotropy MR‐PRESSO test. Results random‐effects IVW indicated that genetically predicted associated with increased risk (OR: 1.432; 95% CI: 1.097–1.868; p = 0.008), this remained significant in validation dataset 1.444; 1.208–1.725; < 0.001). Mediation analysis homogeneous populations showed IDD partially mediates SS, mediation ratio 38.39% (95% 2.66–74.13). Sensitivity analyses supported our conclusions. Conclusions provides evidence determined acting as partial mediator. These findings underscore importance spine‐protective behaviors early prevention strategies patients mitigate risk.

Language: Английский

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Engineered Cell Membrane‐Coated Keratin Nanoparticles Attenuated Intervertebral Disc Degeneration by Remodeling the Disc Microenvironment

Advanced Healthcare Materials, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Abstract Characterized by a cascade of profound changes in nucleus pulposus (NP) cells, extracellular matrix (ECM), and biomechanics, intervertebral disc degeneration is common multifactorial condition that may lead to various degenerative lumbar disorders. Therapeutic strategies targeting single factor have shown limited efficacy treating degeneration, approaches address multiple pathological ingredients are barely reported. In this study, engineered cell membrane‐encapsulated keratin nanoparticles developed simultaneously alleviate NP senescence promote ECM remodeling. To achieve this, salivary acid glycoengineered adipose mesenchymal stem membranes used coat keratin, core protein for structural support cellular protection. The synthesized membrane‐coated (MKNs) effectively protected mitochondrial integrity cells from oxidative stress‐induced damage. Moreover, MKNs modulate metabolism attenuate senescence. addition, activate integrins at the membrane enhance interactions between ECM, resulting increased anabolism decreased catabolism. proposed multi‐targeted strategy block cycle inside efficacious potential clinical application.

Language: Английский

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Microneedles Loaded with Nitric-Oxide Driven Nanomotors Improve Force-Induced Efferocytosis Impairment and Sterile Inflammation by Revitalizing Macrophage Energy Metabolism

ACS Nano, Journal Year: 2025, Volume and Issue: unknown

Published: March 2, 2025

Mechanical force initiates sterile inflammation, a process implicated in diverse physiological and pathological processes. The timely clearance of apoptotic cells by macrophages via efferocytosis is crucial for the proper resolution inflammation averting excessive tissue damage. Despite this, specific role underlying mechanisms mechanical on macrophage remain obscure. By integrating bioinformatics metabolomics analyses, we uncovered how disrupts "arginine metabolism─TCA cycle─mitochondrial function" metabolic cascade, thereby impairing intensifying inflammation. Notably, discovered that elevating l-arginine levels can ameliorate these crises restoring energy metabolism. Leveraging this insight, engineered microneedle drug delivery system loaded with nitric-oxide driven nanomotors (MSN-LA@MNs) targeted l-arginine. active component, MSN-LA, exploits heightened expression inducible nitric oxide synthase (iNOS) force-loaded tissues as chemoattractant, harnessing NO generated from iNOS-catalyzed autonomous propulsion. In force-induced rat orthodontic tooth movement (OTM) model, confirmed MSN-LA@MNs enhance and, under iNOS guidance, dynamically modulate OTM, thus facilitating OTM process. Collectively, our findings elucidate previously unclear mechanistic links between force, efferocytosis, vantage point, offering promising strategy modulating force-related biological processes such OTM.

Language: Английский

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Nucleus pulposus cell-mimicking nanoparticles for cell-specific HIF1A editing to modulate SASP-mediated disc inflammation via autophagy activation

Acta Biomaterialia, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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