Ultrasound-triggered in situ gelation with ROS-controlled drug release for cartilage repair

Materials Horizons, Год журнала: 2023, Номер 10(9), С. 3507 - 3522

Опубликована: Янв. 1, 2023

Cartilage defects are usually caused by acute trauma and chronic degeneration. However, it is still a great challenge to improve the repair of articular cartilage due limited self-regeneration capacity such defects. Herein, novel ROS-responsive in situ nanocomposite hydrogel loaded with kartogenin (KGN) bone marrow-derived stem cells (BMSCs) was designed constructed via enzymatic reaction fibrinogen thrombin. Meanwhile, thioketal (TK)-based liposome synthesized load chondrogenesis-inducing factor KGN, bioenzyme thrombin an ultrasound-sensitive agent PpIX. Under ultrasound stimulation, TK-based destroyed, followed gelation Moreover, sustained release KGN realized regulating conditions. Importantly, ROS generation within microenvironment fibrin significantly promoted chondrogenic differentiation BMSCs Smad5/mTOR signalling pathway effectively improved regeneration rat defect model. Overall, ROS-controlled drug has potential for efficient repair.

Язык: Английский

---

Inflammatory Fibroblast‐Like Synoviocyte‐Derived Exosomes Aggravate Osteoarthritis via Enhancing Macrophage Glycolysis

Advanced Science, Год журнала: 2024, Номер 11(14)

Опубликована: Фев. 11, 2024

Abstract The severity of osteoarthritis (OA) and cartilage degeneration is highly associated with synovial inflammation. Although recent investigations have revealed a dysregulated crosstalk between fibroblast‐like synoviocytes (FLSs) macrophages in the pathogenesis synovitis, limited knowledge available regarding involvement exosomes. Here, increased exosome secretion observed FLSs from OA patients. Notably, internalization inflammatory FLS‐derived exosomes (inf‐exo) can enhance M1 polarization macrophages, which further induces an OA‐like phenotype co‐cultured chondrocytes. Intra‐articular injection inf‐exo synovitis exacerbates progression murine models. In addition, it demonstrated that stimulation triggers activation glycolysis. Inhibition glycolysis using 2‐DG successfully attenuates excessive triggered by inf‐exo. Mechanistically, HIF1A identified as determinant transcription factor, inhibition which, both pharmacologically or genetically, relieves macrophage inflammation inf‐exo‐induced hyperglycolysis. Furthermore, vivo administration inhibitor alleviates experimental OA. results provide novel insights into pathogenesis, suggesting dysfunction represents attractive target for therapy.

Язык: Английский

---

TREM2 promotes macrophage polarization from M1 to M2 and suppresses osteoarthritis through the NF-κB/CXCL3 axis

International Journal of Biological Sciences, Год журнала: 2024, Номер 20(6), С. 1992 - 2007

Опубликована: Янв. 1, 2024

Objective: Osteoarthritis (OA) is the most prominent chronic arthritic disease, affecting over 3 billion people globally.Synovial macrophages, as immune cells, play an essential role in cartilage damage OA.Therefore, regulating macrophages crucial for controlling pathological changes OA.Triggering receptor expressed on myeloid cells 2 (TREM2), cell surfaces, such and dendritic has suppressed inflammation regulated M2 macrophage polarization but demonstrated unknown synovial OA.This study aimed to investigate TREM2 expression downregulation OA mice macrophages.Furthermore, trend of was associated with polarization-related molecule mice.Results: We used knockout (TREM2-KO) observe that deficiency significantly exacerbated joint response mice, thereby accelerating disease progression.Separating chondrocytes from TREM2-KO co-cultivating them increased chondrocyte apoptosis inhibited proliferation.Further, also enhanced phosphatidylinositol 3-kinase(PI3K)/AKT signaling pathway activation, increasing nuclear factor kappa light chain enhancer activated B (NF-κB) C-X-C Motif Chemokine Ligand (CXCL3) expression.Furthermore, NF-κB inhibition arthritis effectively alleviating deficiency-related adverse effects chondrocytes.Notably, knocking down CXCL3 inhibits inflammatory promotes proliferation.Intravenous recombinant protein (soluble TREM2, sTREM2) injection markedly M1 improves tissue pathology OA.Conclusion: Our reveals during by NF-κB/CXCL3 axis regulation, improving state OA.

Язык: Английский

---

Mechanochemically Reprogrammed Interface Orchestrates Neutrophil Bactericidal Activity and Apoptosis for Preventing Implant‐Associated Infection

Advanced Materials, Год журнала: 2024, Номер 36(16)

Опубликована: Янв. 2, 2024

Abstract The onset of implant‐associated infection (IAI) triggers a cascade immune responses, which are initially dominated by neutrophils. Bacterial aggregate formation and hypoxic microenvironment, occur shortly after implantation, may be two major risk factors that impair neutrophil function lead to IAI. Here, the implant surface with phytic acid–Zn 2+ coordinated TiO 2 nanopillar arrays (PA–Zn@TiNPs) oxygen self‐supporting CaO nanoparticles, named as CPZTs, is mechanochemically reprogrammed. engineered CPZTs interface integrates multiple properties inhibit nascent biofilm, encompassing antibacterial adhesion, mechanobactericidal effect, chemobiocidal effect. Meanwhile, continuous oxygenation fuels neutrophils reactive species (ROS) for efficient bacterial elimination on inside Furthermore, this modulation strategy accelerates apoptosis promotes M2 macrophage‐mediated osteogenesis both in vitro rat model In conclusion, targeting immunomodulation practical effective prevent IAI promote bone–implant integration.

Язык: Английский

---

MMP13-targeted siRNA-loaded micelles for diagnosis and treatment of posttraumatic osteoarthritis

Bioactive Materials, Год журнала: 2024, Номер 37, С. 378 - 392

Опубликована: Апрель 23, 2024

Posttraumatic osteoarthritis (PTOA) patients are often diagnosed by X-ray imaging at a middle-late stage when drug interventions less effective. Early PTOA is characterized overexpressed matrix metalloprotease 13 (MMP13). Herein, we constructed an integrated diagnosis and treatment micelle modified with MMP13 enzyme-detachable, cyanine 5 (Cy5)-containing PEG, black hole quencher-3 (BHQ3), cRGD ligands loaded siRNA silencing (siM13), namely ERMs@siM13. ERMs@siM13 could be cleaved in the diseased cartilage tissues to detach PEG shell, causing exposure. Accordingly, ligand exposure promoted uptake chondrocytes binding cell surface αvβ3 integrin, increasing intracellular siM13 delivery for on-demand downregulation. Meanwhile, Cy5 fluorescence was restored detaching from BHQ3-containing micelle, precisely reflecting state. In particular, intensity of generated that hinged on levels reflect severity, enabling physicians adjust therapeutic regimen. Finally, murine model, diagnose early-stage PTOA, perform timely interventions, monitor OA progression level during through real-time detection MMP13. Therefore, represents appealing approach theranostics.

Язык: Английский

---

Hypoxia causes trophoblast cell ferroptosis to induce miscarriage through lnc-HZ06/HIF1α-SUMO/NCOA4 axis

Redox Biology, Год журнала: 2024, Номер 70, С. 103073 - 103073

Опубликована: Фев. 2, 2024

Defects of human trophoblast cells may induce miscarriage (abnormal early embryo loss), which is generally regulated by lncRNAs. Ferroptosis a newly identified iron-dependent programmed cell death. Hypoxia an important and unavoidable feature in mammalian cells. However, whether hypoxia might ferroptosis then miscarriage, as well lncRNA, was completely unknown. In this work, we discovered at the first time that could result miscarriage. We also novel lncRNA (lnc-HZ06) simultaneously (indicated HIF1α protein), ferroptosis, mechanism, HIF1α-SUMO, instead itself, primarily acted transcription factor to promote NCOA4 (ferroptosis indicator) hypoxic Lnc-HZ06 promoted SUMOylation suppressing SENP1-mediated deSUMOylation. HIF1α-SUMO lnc-HZ06 transcription. Thus, both formed positive auto-regulatory feedback loop. This loop up-regulated cells, RM villous tissues, placental tissues hypoxia-treated mice, further induced up-regulating HIF1α-SUMO-mediated Furthermore, knockdown either murine lnc-hz06 or Ncoa4 efficiently suppress alleviate mouse model. Taken together, study provided new insights understanding regulatory roles lnc-HZ06/HIF1α-SUMO/NCOA4 axis among hypoxia, offered effective approach for treatment against

Язык: Английский

---

The role of HIF-1α in hypoxic metabolic reprogramming in osteoarthritis

Pharmacological Research, Год журнала: 2025, Номер unknown, С. 107649 - 107649

Опубликована: Фев. 1, 2025

The joint dysfunction caused by osteoarthritis (OA) is increasingly becoming a major challenge in global healthcare, and there currently no effective strategy to prevent the progression of OA. Therefore, better elucidating relevant mechanisms OA occurrence development will provide theoretical basis for formulating new prevention control strategies. Due long-term exposure cartilage tissue hypoxic microenvironment joints, metabolic reprogramming changes occur. Hypoxia-inducible factor-1alpha (HIF-1α), as core gene regulating hypoxia response vivo, plays an important regulatory role metabolism chondrocytes. HIF-1α adapts such glycolysis, oxidative phosphorylation (OXPHOS), amino acid metabolism, lipid In addition, also regulates macrophage polarization synovial inflammation, chondrocytes degeneration extracellular matrix (ECM) degradation, subchondral bone remodeling angiogenesis OA, affects pathophysiological Consequently, regulation has become therapeutic target this article reviews mechanism affecting chondrocyte reprogramming, focusing on summarizes potential ingredients or targets targeting order more beneficial treatment clinical drugs.

Язык: Английский

---

Regulating Chondro‐Bone Metabolism for Treatment of Osteoarthritis via High‐Permeability Micro/Nano Hydrogel Microspheres

Advanced Science, Год журнала: 2023, Номер 11(5)

Опубликована: Дек. 11, 2023

Abstract Destruction of cartilage due to the abnormal remodeling subchondral bone (SB) leads osteoarthritis (OA), and restoring chondro‐bone metabolic homeostasis is key treatment OA. However, traditional intra‐articular injections for OA cannot directly break through barrier reach SB. In this study, hydrothermal method used synthesize ultra‐small size (≈5 nm) selenium‐doped carbon quantum dots (Se‐CQDs, SC), which conjugated with triphenylphosphine (TPP) create TPP‐Se‐CQDs (SCT). Further, SCT dynamically complexed hyaluronic acid modified aldehyde methacrylic anhydride (AHAMA) construct highly permeable micro/nano hydrogel microspheres (SCT@AHAMA) homeostasis. vitro experiments confirmed that selenium atoms scavenged reactive oxygen species (ROS) from mitochondria mononuclear macrophages, inhibited osteoclast differentiation function, suppressed early chondrocyte apoptosis maintain a balance between matrix synthesis catabolism. vivo further demonstrated delivery system osteoclastogenesis H‐vessel invasion, thereby regulating initiation process inhibiting degeneration in conclusion, based on facilitate efficient penetration articular SB regulate metabolism treatment.

Язык: Английский

---

Osteoarthritis year in review 2023: Biology

Osteoarthritis and Cartilage, Год журнала: 2023, Номер 32(2), С. 148 - 158

Опубликована: Ноя. 7, 2023

Great progress continues to be made in our understanding of the multiple facets osteoarthritis (OA) biology. Here, we review major advances this field and towards therapy development over past year, highlighting a selection relevant published literature from PubMed search covering year end April 2022 2023. The selected articles have been arranged themes. These include 1) molecular regulation articular cartilage implications for OA, 2) mechanisms subchondral bone remodelling, 3) role synovium inflammation, 4) age-related changes including matrix stiffening, cellular senescence, mitochondrial dysfunction, metabolic impaired autophagy, 5) peripheral OA pain. Progress responsible aspects biology is unravelling novel therapeutic targets disease modification.

Язык: Английский

---

Tantalum Particles Promote M2 Macrophage Polarization and Regulate Local Bone Metabolism via Macrophage‐Derived Exosomes Influencing the Fates of BMSCs

Advanced Healthcare Materials, Год журнала: 2024, Номер 13(17)

Опубликована: Март 18, 2024

In this study, the regulatory role and mechanisms of tantalum (Ta) particles in bone tissue microenvironment are explored. Ta particle deposition occurs both clinical samples animal tissues following porous implantation. Unlike titanium (Ti) promoting M1 macrophage (Mϕ) polarization, regulating calcium signaling pathways M2 Mϕ polarization. Ta-induced enhances marrow-derived mesenchymal stem cells (BMSCs) proliferation, migration, osteogenic differentiation through exosomes (Exo) by upregulating miR-378a-3p/miR-221-5p downregulating miR-155-5p/miR-212-5p. suppress pro-inflammatory resorption effects Ti vivo vitro. a rat femoral condyle defect model, artificial loaded with promotes endogenous polarization toward at site, accelerating repair. conclusion, modulate influence BMSCs capacity Exo secreted Mϕ, providing insights for potential repair applications.

Язык: Английский

---