Reprogramming of Mitochondrial Respiratory Chain Complex by Targeting SIRT3‐COX4I2 Axis Attenuates Osteoarthritis Progression

Advanced Science, Год журнала: 2023, Номер 10(10)

Опубликована: Янв. 22, 2023

Mitochondrial homeostasis is of great importance for cartilage integrity and associated with the progression osteoarthritis (OA); however, underlying mechanisms are unknown. This study aims to investigate role mitochondrial deacetylation reaction mechanistic relationship OA development. Silent mating type information regulation 2 homolog 3 (SIRT3) expression has a negative correlation severity in both human arthritic mice inflammatory chondrocytes. Global SIRT3 deletion accelerates pathological phenotype post-traumatic mice, as evidenced by extracellular matrix collapse, osteophyte formation, synovial macrophage M1 polarization. Mechanistically, prevents targeting deacetylating cytochrome c oxidase subunit 4 isoform (COX4I2) maintain at post-translational level. The activation honokiol restores metabolic equilibrium protects from development OA. Collectively, loss essential OA, whereas SIRT3-mediated proteins COX4I2 rescues OA-impaired respiratory chain functions improve phenotype. Herein, induction provides novel therapeutic candidate treatment.

Язык: Английский

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Enhanced SIRT3 expression restores mitochondrial quality control mechanism to reverse osteogenic impairment in type 2 diabetes mellitus

Bone Research, Год журнала: 2025, Номер 13(1)

Опубликована: Март 3, 2025

Abstract Osteoporosis represents a prevalent and debilitating comorbidity in patients diagnosed with type 2 diabetes mellitus (T2DM), which is characterized by suppressed osteoblast function disrupted bone microarchitecture. In this study, we utilized male C57BL/6 J mice to investigate the role of SIRT3 T2DM. Decreased expression impaired mitochondrial quality control mechanism are observed both vitro vivo models Mechanistically, suppression results hyperacetylation FOXO3, hindering activation PINK1/PRKN mediated mitophagy pathway resulting accumulation dysfunctional mitochondria. Genetical overexpression or pharmacological restores deacetylation status thus facilitating ameliorating osteogenic impairment Collectively, our findings highlight fundamental regulatory control, crucial for maintaining homeostasis These insights not only enhance understanding molecular mechanisms underlying diabetic osteoporosis but also identify as promising therapeutic target osteoporosis.

Язык: Английский

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3D-bioprinted anisotropic bicellular living hydrogels boost osteochondral regeneration via reconstruction of cartilage–bone interface

The Innovation, Год журнала: 2023, Номер 5(1), С. 100542 - 100542

Опубликована: Ноя. 20, 2023

Reconstruction of osteochondral (OC) defects represents an immense challenge due to the need for synchronous regeneration special stratified tissues. The revolutionary innovation bioprinting provides a robust method precise fabrication tissue-engineered OCs with hierarchical structure; however, their spatial living cues simultaneous fulfilment osteogenesis and chondrogenesis reconstruct cartilage-bone interface OC are underappreciated. Here, inspired by natural bilayer features, anisotropic bicellular hydrogels (ABLHs) simultaneously embedding articular cartilage progenitor cells (ACPCs) bone mesenchymal stem (BMSCs) in layers were precisely fabricated via two-channel extrusion bioprinting. optimum formulation 7% GelMA/3% AlgMA hydrogel bioink was demonstrated, excellent printability at room temperature maintained high cell viability. Moreover, chondrogenic ability ACPCs osteogenic BMSCs demonstrated vitro, confirming inherent differential regulation ABLHs. In addition, ABLHs exhibited satisfactory subchondral vivo. Compared homogeneous hydrogels, neo-cartilage neo-bone augmented 23.5% 20.8%, respectively, more important, harmonious achieved well-tuned cartilage-bone-vessel crosstalk. We anticipate that such strategy tissue-mimetic ABLH means is capable spatiotemporal cell-driven regeneration, offering insights into materials reconstruction complex organ defects.

Язык: Английский

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Cartilage-inspired self-assembly glycopeptide hydrogels for cartilage regeneration via ROS scavenging

Bioactive Materials, Год журнала: 2023, Номер 32, С. 319 - 332

Опубликована: Окт. 18, 2023

Cartilage injury represents a frequent dilemma in clinical practice owing to its inherently limited self-renewal capacity. Biomimetic strategy-based engineered biomaterial, capable of coordinated regulation for cellular and microenvironmental crosstalk, provides an adequate avenue boost cartilage regeneration. The level oxidative stress microenvironments is verified be vital tissue regeneration, yet it often overlooked biomaterials Herein, inspired by natural architecture, fibril-network glycopeptide hydrogel (Nap-FFGRGD@FU), composed marine-derived polysaccharide fucoidan (FU) naphthalenephenylalanine-phenylalanine-glycine-arginine-glycine-aspartic peptide (Nap-FFGRGD), was presented through simple supramolecular self-assembly approach. Nap-FFGRGD@FU hydrogels exhibit native cartilage-like characterized interwoven collagen fibers attached proteoglycans. Beyond structural simulation, fucoidan-exerted robust biological effects Arg-Gly-Asp (RGD) sequence-provided cell attachment sites realized functional reinforcement, synergistically promoted extracellular matrix (ECM) production reactive oxygen species (ROS) elimination, thus contributing chondrocytes-ECM harmony. In vitro co-culture with not only facilitated ECM anabolic metabolism but also scavenged ROS accumulation chondrocytes. Mechanistically, the chondro-protective induced rely on activation endogenous antioxidant pathways associated nuclear factor erythroid 2-related 2 (NRF2). vivo implantation successfully improved de novo generation 1.65-fold, concomitant coordinately restructured subchondral bone structure. Collectively, our ingeniously crafted bionic simultaneously rewired chondrocytes' function augmenting rebuilt microenvironment via preserving redox equilibrium, holding great potential engineering.

Язык: Английский

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Cellular senescence in skeletal disease: mechanisms and treatment

Cellular & Molecular Biology Letters, Год журнала: 2023, Номер 28(1)

Опубликована: Окт. 27, 2023

Abstract The musculoskeletal system supports the movement of entire body and provides blood production while acting as an endocrine organ. With aging, balance bone homeostasis is disrupted, leading to loss degenerative diseases, such osteoporosis, osteoarthritis, intervertebral disc degeneration. Skeletal diseases have a profound impact on motor cognitive abilities elderly, thus creating major challenge for both global health economy. Cellular senescence caused by various genotoxic stressors results in permanent cell cycle arrest, which considered be underlying mechanism aging. During senescent cells (SnCs) tend aggregate trigger chronic inflammation releasing senescence-associated secretory phenotypic factors. Multiple signalling pathways are involved regulating cellular marrow microenvironments. Targeted SnCs alleviate age-related diseases. However, association between remains unclear. This review summarises fundamental role skeletal highlights that mediate senescence, discusses potential therapeutic strategies targeting SnCs. Graphical

Язык: Английский

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Photothermal Microneedle Hydrogel Patch for Refractory Soft Tissue Injuries through Thermosensitized Anti‐Inflammaging Modulation

Small Structures, Год журнала: 2024, Номер 5(5)

Опубликована: Фев. 22, 2024

Soft tissue injuries (STIs) are the most common cause of extremity pain and motion dysfunction. Persistent inflammatory activation immune cells characterized by senescence‐associated secretory phenotype (SASP) mitochondrial stress considered primary causes STIs, a pathological process also termed inflammaging. Meanwhile, scavenging excessive “cellular waste” in inflammaging microenvironment further activating repair processes remain elusive. Herein, an anti‐inflammaging photothermal hydrogel microneedle patch for treating STIs is developed. Taurine‐loaded Prussian blue nanoparticles (Taurine@PB) encapsulated methacrylate‐based hyaluronic acid (HAMA) fabricated into taurine@PB@HAMA@microneedles (TPH@MN) patches. The acidic chronic inflammation mild effects promote taurine release immunomodulation, inhibiting via SIRT3‐NF‐κB axis to glycolytic metabolic neutrophils reprogramming toward oxidative phosphorylation metabolism. Furthermore, TPH@MN activates macrophage efferocytosis initiates repair. In mouse models diabetic wounds tibialis anterior (TA) muscle injury, inhibits SASP expression promotes healing through thermosensitized immunomodulation. summary, circumvents side systemic administration, providing new translatable options treatment modalities patients suffering from worldwide.

Язык: Английский

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Sirtuins in kidney diseases: potential mechanism and therapeutic targets

Cell Communication and Signaling, Год журнала: 2024, Номер 22(1)

Опубликована: Фев. 12, 2024

Abstract Sirtuins, which are NAD + -dependent class III histone deacetylases, involved in various biological processes, including DNA damage repair, immune inflammation, oxidative stress, mitochondrial homeostasis, autophagy, and apoptosis. Sirtuins essential regulators of cellular function organismal health. Increasing evidence suggests that the development age-related diseases, kidney is associated with aberrant expression sirtuins, regulation sirtuins activity can effectively improve delay progression disease. In this review, we summarise current studies highlighting role renal diseases. First, discuss sirtuin family members their main mechanisms action. We then outline possible roles cell types Finally, compounds activate or inhibit consequently ameliorate conclusion, targeted modulation a potential therapeutic strategy for

Язык: Английский

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Cerium Dioxide Nanoparticles‐Based Inspector Enhances Mitochondrial Quality Control to Maintain Chondrocyte Homeostasis in Osteoarthritis Therapy

Advanced Healthcare Materials, Год журнала: 2025, Номер unknown

Опубликована: Март 3, 2025

Abstract Imbalanced mitochondrial quality control is strongly linked to the onset and development of osteoarthritis (OA). However, current research primarily focuses on local cartilage repair phenotype maintenance, lacking a systematic approach subcellular control. To address this, present study proposes strategy based nanozyme hydrogel microspheres (“mitochondrial inspector”), constructed through electrostatic self‐assembly, incorporation dynamic diselenide bonds, microfluidic technology. The oxidative stress microenvironment improved by cerium dioxide nanoparticles combined with metformin activate autophagy clear persistently dysfunctional mitochondria, thereby inhibiting OA progression. In vitro results showed that “mitochondrial inspector” not only significantly chondrocytes, but also efficiently scavenged damaged increased membrane potential over 20‐fold, notably function chondrocyte homeostasis. rat model, minimally invasive intra‐articular injection effectively regulated quality, alleviated matrix degradation, reduced osteophyte formation ≈80%, Mankin score for damage 70%. summary, this presents novel microsphere‐based treatment OA, providing new insights therapies other aging‐related diseases.

Язык: Английский

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SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch

Bone Research, Год журнала: 2025, Номер 13(1)

Опубликована: Март 14, 2025

Язык: Английский

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Retuning Mitochondrial Apoptosis/Mitophagy Balance via SIRT3‐Energized and Microenvironment‐Modulated Hydrogel Microspheres to Impede Osteoarthritis

Advanced Healthcare Materials, Год журнала: 2023, Номер 12(32)

Опубликована: Сен. 12, 2023

Full-range therapeutic regimens for osteoarthritis (OA) should consider organs (joints)-tissues (cartilage)-cells (chondrocytes)-organelles cascade, of which the subcellular mitochondria dominate eukaryotic cells' fate, and thus causally influence OA progression. However, dynamic regulation mitochondrial rise demise in impaired chondrocytes exact role metronome sirtuins 3 (SIRT3) is not clarified. Herein, are treated with SIRT3 natural agonist dihydromyricetin (DMY) or chemical antagonist 3-TYP, respectively, to demonstrate positive action on preserving cartilage extracellular matrix (ECM). Molecular mechanical investigations disclose that SIRT3-induced chondroprotection depended repression apoptosis (mtApoptosis) activation mitophagy. Inspired by high-level proteinases reactive oxygen species (ROS) environment, anchoring gelatin methacrylate (GelMA) benzenediboronic acid (PBA) hyaluronic (HAMA) microfluidic technology, a dual-responsive hydrogel microsphere laden DMY tactfully fabricated named as DMY@HAMA-GelMA-PBA (DMY@HGP). In vivo injection DMY@HGP ameliorated abrasion subchondral bone sclerosis, well promoted motor function recovery post-traumatic (PTOA) model via recouping endogenous mtApoptosis mitophagy balance. Overall, this study unveils novel dynamic-oriented strategy, holding great promise precision treatment OA.

Язык: Английский

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