Mitochondrial-Oriented Injectable Hydrogel Microspheres Maintain Homeostasis of Chondrocyte Metabolism to Promote Subcellular Therapy in Osteoarthritis

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

Published: Jan. 1, 2024

Subcellular mitochondria serve as sensors for energy metabolism and redox balance, the dynamic regulation of functional dysfunctional plays a crucial role in determining cells' fate. Selective removal at subcellular level can provide chondrocytes with to prevent degeneration, thereby treating osteoarthritis. Herein, achieve an ideal therapy, cartilage affinity peptide (WYRGRL)-decorated liposomes loaded mitophagy activator (urolithin A) were integrated into hyaluronic acid methacrylate hydrogel microspheres through microfluidic technology, named HM@WY-Lip/UA, that could efficiently target selectively remove mitochondria. As result, this system demonstrated advantage function restoration, reactive oxygen species scavenging, cell survival rescue, chondrocyte homeostasis maintenance increasing mitophagy. In rat post-traumatic osteoarthritis model, intra-articular injection HM@WY-Lip/UA ameliorated matrix degradation, osteophyte formation, subchondral bone sclerosis 8 weeks. Overall, study indicated provided protective effect on degeneration efficacious clinically relevant manner, mitochondrial-oriented strategy has great potential therapy

Language: Английский

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Safety and efficacy of mesenchymal stromal cells mitochondria transplantation as a cell-free therapy for osteoarthritis

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

Published: Jan. 7, 2025

The inflammatory responses from synovial fibroblasts and macrophages the mitochondrial dysfunction in chondrocytes lead to oxidative stress, disrupt extracellular matrix (ECM) homeostasis, accelerate deterioration process of articular cartilage osteoarthritis (OA). In recent years, it has been proposed that mesenchymal stromal cells (MSC) transfer their functional mitochondria damaged response cellular becoming one mechanisms underpinning therapeutic effects. Therefore, we hypothesize a novel cell-free treatment for OA could involve direct transplantation, restoring both homeostasis. Mitochondria were isolated Umbilical Cord (UC)-MSC (Mito-MSC) characterized based on morphology, phenotype, functions, ability be internalized by different cells. Furthermore, transcriptional changes following uptake evaluated using an Affymetrix analysis, Lastly, dose dependence efficacy, biodistribution immunogenicity Mito-MSC assessed vivo, through intra-articular injection male C57BL6 mice collagenase-induced (CIOA) model. Our findings demonstrate integrity efficiently transferred into chondrocytes, macrophages, fibroblasts. Moreover, transcriptomic analysis showed upregulation genes involved stress such as DNA reparative machinery antiviral responses. Finally, transplantation yielded significant reductions joint mineralization, hallmark progression, well improvements OA-related histological signs, with lower exhibiting better efficacy. was detected within knee up 24 h post-injection without eliciting CIOA mice. Collectively, our results reveal derived MSC are key retained generating immune mitigating degradation OA, probably restorative effect triggered chondrocytes.

Language: Английский

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Targeted activation on Bnip3 enhances mitophagy to prevent the progression of osteoarthritis

Journal of Orthopaedic Translation, Journal Year: 2025, Volume and Issue: 51, P. 242 - 255

Published: March 1, 2025

The production of reactive oxygen species (ROS) and mitochondrial dysfunction in chondrocytes are closely related to cartilage degeneration the procedure osteoarthritis (OA). Mitophagy is responsible for scavenging ROS dysfunctional mitochondria considered a key therapeutic target treatment OA. Tiopronin, classic thiol antioxidant, has been widely studied various oxidative stress-related diseases. expression mitophagy (PINK1, PARKIN, TOMM20) intact damaged OA patients was analyzed by Western blot histological analysis. RNA sequencing (RNA-seq) analysis performed explore molecular mechanism tiopronin regulating chondrocytes, then find specific tiopronin. effects were evaluated model induced destabilisation medial meniscus (DMM), degenerative with primary from mouse human explants experiment. downstream mechanisms further investigated si-RNA knockdown mitophagy-related proteins. level negatively correlated severity We revealed that promoted anabolism extracellular matrix (ECM) hyaline alleviates vitro vivo strengthening mitophagy. Moreover, strongly activated Bnip3, protein anchored membrane, subsequently enhanced Pink1/Parkin signaling pathway. These findings indicate Bnip3-Pink1-Parkin pathway, targeted tiopronin, plays role inhibiting progression As classical drug clinic, developed new approach via this study. Based significant efficient effect degermation delay OA, it believed may become an effective candidate clinical settings.

Language: Английский

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Fibrotic pathways and fibroblast-like synoviocyte phenotypes in osteoarthritis

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: June 4, 2024

Osteoarthritis (OA) is the most common form of arthritis, characterized by osteophyte formation, cartilage degradation, and structural cellular alterations synovial membrane. Activated fibroblast-like synoviocytes (FLS) membrane have been identified as key drivers, secreting humoral mediators that maintain inflammatory processes, proteases cause bone destruction, factors drive fibrotic processes. In normal tissue repair, processes are terminated after damage has repaired. fibrosis, remodeling wound healing exaggerated prolonged. Various stressors, including aging, joint instability, inflammation, lead to micro lesions within tissue. One result reduced production fluid (lubricants), which reduces lubricity areas, leading damage. tissue, a wound-healing cascade initiated activating macrophages, Th2 cells, FLS. The latter can be divided into two major populations. destructive thymocyte differentiation antigen (THY)1 ─ phenotype restricted lining layer. contrast, THY1 + sublining layer classified an invasive one with immune effector function driving synovitis. exact mechanisms involved in transition fibroblasts myofibroblast-like drives fibrosis remain unclear. review provides overview phenotypes spatial distribution FLS OA, describes fibroblast myofibroblast activation, metabolic cells.

Language: Английский

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From dysfunction to healing: advances in mitochondrial therapy for Osteoarthritis

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Nov. 11, 2024

Osteoarthritis (OA) is a chronic degenerative joint condition characterised by cartilage deterioration and changes in bone morphology, resulting pain impaired mobility. Investigation into the pathophysiological mechanisms underlying OA has highlighted significance of mitochondrial dysfunction its progression. Mitochondria, which are cellular organelles, play crucial role regulating energy metabolism, generating reactive oxygen species, facilitating essential biological processes including apoptosis. In recent years, utilisation exogenous drugs MT to improve function chondrocytes shown great promise treatment. Numerous studies have investigated potential stem cells extracellular vesicles transfer. This review aims explore assess progress utilising transfer as therapeutic approach for this disease.

Language: Английский

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In Vivo and In Vitro Evaluation of the Feasibility and Safety Profiles of Intraarticular Transplantation of Mitochondria for Future Use as a Therapy for Osteoarthritis

Cells, Journal Year: 2025, Volume and Issue: 14(3), P. 151 - 151

Published: Jan. 21, 2025

Osteoarthritis (OA) is the most common rheumatologic disease and a major cause of pain disability in older adults. No efficient treatment currently available. Mitochondrial dysfunction chondrocytes drives molecular dysregulation OA pathogenesis. Recently, mitochondrial transfer to had been described, enabling transplant mitochondria as new avenue modify process, although evidence on its feasibility safety remains limited.The primary objective this study was demonstrate intra-articular transplantation. Mitochondria were isolated from liver using procedure described by Preble coworkers combined with magnetic beads coupled anti-TOM22 antibodies. The organelles obtained analyzed determine their purity viability. viability administration into articular tissues well integration distribution transplanted within joint both vitro vivo models. We established an efficient, reproducible, effective, rapid protocol for isolating liver. high viability, yield, purity. injected tissue Functional detected extracellular matrix cartilage, menisci synovium. Our results establish safe viable isolation injection. methodology findings presented here pave way future studies osteoarthritis models validate transplantation potentially effective OA.

Language: Английский

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Advanced Machine Learning for Comparative Synovial Fluid Analysis in Osteoarthritis and Rheumatoid Arthritis

Metabolites, Journal Year: 2025, Volume and Issue: 15(2), P. 112 - 112

Published: Feb. 10, 2025

Osteoarthritis (OA) and rheumatoid arthritis (RA) are joint diseases that share similar clinical features but have different etiologies, making a differential diagnosis particularly challenging. Background/Objectives: Utilizing advanced machine learning (ML) techniques on metabolomic data, this study aimed to identify key metabolites in synovial fluid (SF) could aid distinguishing between OA RA. Methods: Metabolite data from the MetaboLights database (MTBLS564), analyzed using nuclear magnetic resonance (NMR), were processed normalization, principal component analysis (PCA), partial least squares discriminant (PLS-DA) reveal prominent clustering. Results: Decision forests random forest classifiers, optimized genetic algorithms (GAs), highlighted selection of few metabolites—primarily glutamine, pyruvate, proline—with significant discriminative power. A Shapley additive explanations (SHAP) confirmed these be pivotal predictors, offering streamlined approach for diagnostics. Conclusions: Our findings suggest minimal set can effectively relied upon distinguish RA, supported by an ML model achieving high accuracy. This workflow streamline diagnostic efficiency enhance decision-making rheumatology.

Language: Английский

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The Interplay of Aging and PANoptosis in Osteoarthritis Pathogenesis: Implications for Novel Therapeutic Strategies

Journal of Inflammation Research, Journal Year: 2025, Volume and Issue: Volume 18, P. 1951 - 1967

Published: Feb. 1, 2025

Abstract: Osteoarthritis (OA) is a common degenerative joint disease characterized by the progressive degradation of articular cartilage, synovial inflammation, and subchondral bone remodeling. This review explores interplay between aging, PANoptosis, inflammation in OA progression. Age-related cellular immune dysfunctions, including senescence, senescence-associated secretory phenotypes (SASPs), immunosenescence, significantly contribute to degeneration. In OA, dysregulated apoptosis, necroptosis, pyroptosis, particularly chondrocytes, exacerbate cartilage damage. Apoptosis, mediated JNK pathway, reduces chondrocyte density, while necroptosis involving RIPK-1/RIPK-3 NLRP3 inflammasome, respectively, amplify destruction. Inflammatory cytokines damage-associated molecular patterns (DAMPs) further enhance these PANoptotic pathways. Current therapeutic strategies primarily focus on anti-inflammatory agents such as non-steroidal drugs (NSAIDs) corticosteroids, with growing interest anti-senescence targeting senescence SASP. Additionally, exploring PANoptosis mechanisms offers potential for innovative treatments. Keywords: osteoarthritis,

Language: Английский

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Application and progress of smart hydrogel microspheres for regulating oxidative stress in osteoarthritis

Chemical Engineering Journal, Journal Year: 2025, Volume and Issue: unknown, P. 160620 - 160620

Published: Feb. 1, 2025

Language: Английский

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Pioglitazone Regulates Chondrocyte Metabolism and Attenuates Osteoarthritis by Activating Peroxisome Proliferator‐Activated Receptor Gamma

Journal of Cellular and Molecular Medicine, Journal Year: 2025, Volume and Issue: 29(4)

Published: Feb. 1, 2025

ABSTRACT Osteoarthritis presents a significant clinical challenge due to its high prevalence and the resultant impairment of patients' motor function. Osteoarthritic chondrocytes are characterised by inflammation metabolic disturbances. Pioglitazone, an agonist peroxisome proliferator‐activated receptor γ (PPAR‐γ), has been demonstrated exert anti‐inflammatory effects across various diseases. This study aims investigate potential protective Pioglitazone on osteoarthritic chondrocytes. An in vitro chondrocyte model was established utilising IL‐1β. The impact extracellular matrix synthesis evaluated through enzyme‐linked immunosorbent assay, immunofluorescence staining Alcian blue staining. affinity for PPAR‐γ investigated using molecular docking techniques. Alterations glycolysis oxidative phosphorylation were examined Seahorse XF Analyser, influence glucose uptake mitochondrial electron transport chain further analysed. gavaged mouse OA anterior cruciate ligament transection evaluate therapeutic efficacy Pioglitazone. Our findings indicate that mitigates osteoarthritis murine models inhibiting expression inflammatory mediators such as TNF‐α, IL‐6 PGE2, preventing degradation aggrecan collagen II. Furthermore, significantly upregulated transporter 1 stabilised proton delivery PPAR‐γ‐dependent manner, thereby enhancing uptake, glycolysis, phosphorylation. These partially reversed antagonist GW9662. can confer chondroprotective benefits activating PPAR‐γ.

Language: Английский

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