Osteoarthritis: pathogenic signaling pathways and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Feb. 3, 2023

Abstract Osteoarthritis (OA) is a chronic degenerative joint disorder that leads to disability and affects more than 500 million population worldwide. OA was believed be caused by the wearing tearing of articular cartilage, but it now commonly referred as whole-joint initiated with biochemical cellular alterations in synovial tissues, which histological structural changes ends up whole tissue dysfunction. Currently, there no cure for OA, partly due lack comprehensive understanding pathological mechanism initiation progression disease. Therefore, better signaling pathways key molecules involved pathogenesis crucial therapeutic target design drug development. In this review, we first summarize epidemiology including its prevalence, incidence burdens, risk factors. We then focus on roles regulation pathways, such Wnt/β-catenin, NF-κB, focal adhesion, HIFs, TGFβ/ΒΜP FGF regulators AMPK, mTOR, RUNX2 onset development OA. addition, factors associated MMPs, ADAMTS/ADAMs, PRG4, are discussed detail. Finally, provide updates current clinical therapies trials biological treatments drugs Research advances basic knowledge cartilage biology will have significant impact translational value developing strategies.

Language: Английский

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Current understanding of osteoarthritis pathogenesis and relevant new approaches

Bone Research, Journal Year: 2022, Volume and Issue: 10(1)

Published: Sept. 20, 2022

Abstract Osteoarthritis (OA) is the most common degenerative joint disease that causes painful swelling and permanent damage to joints in body. The molecular mechanisms of OA are currently unknown. a heterogeneous affects entire joint, multiple tissues altered during development. To better understand pathological OA, new approaches, methods, techniques need be used pathogenesis. In this review, we first focus on epigenetic regulation with particular DNA methylation, histone modification, microRNA regulation, followed by summary several key mediators OA-associated pain. We then introduce innovative have been will continue fields pain, such as CRISPR, scRNA sequencing, lineage tracing. Next, discuss timely updates concerning cell death pathology, including pyroptosis, ferroptosis, autophagy, well their individual roles potential targets treating OA. Finally, our review highlights directions role synovial lymphatic system An improved understanding pathogenesis aid development more specific effective therapeutic interventions for

Language: Английский

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Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: July 22, 2022

Quercetin, a naturally non-toxic flavonoid within the safe dose range with antioxidant, anti-apoptotic and anti-inflammatory properties, plays an important role in treatment of aging-related diseases. Sirtuin 1 (SIRT1), member NAD+-dependent deacetylase enzyme family, is extensively explored as potential therapeutic target for attenuating aging-induced disorders. SIRT1 possess beneficial effects against diseases such Alzheimer's disease (AD), Parkinson's (PD), Huntington's (HD), Depression, Osteoporosis, Myocardial ischemia (M/I) reperfusion (MI/R), Atherosclerosis (AS), Diabetes. Previous studies have reported that aging increases tissue susceptibility, whereas, regulates cellular senescence multiple processes, including SIRT1/Keap1/Nrf2/HO-1 SIRTI/PI3K/Akt/GSK-3β mediated oxidative stress, SIRT1/NF-κB SIRT1/NLRP3 regulated inflammatory response, SIRT1/PGC1α/eIF2α/ATF4/CHOP SIRT1/PKD1/CREB controlled phosphorylation, SIRT1-PINK1-Parkin mitochondrial damage, SIRT1/FoxO autophagy, SIRT1/FoxG1/CREB/BDNF/Trkβ-catenin neuroprotective effects. In this review, we summarized improvement attenuation effect quercetin on relationship between relevant signaling pathways by SIRT1. Moreover, functional regulation markers function, autophagy apoptosis through was discussed. Finally, prospects extracellular vesicles (EVs) loading delivery, SIRT1-mediated EVs signal carriers treating diseases, well discussed ferroptosis alleviation to protect via activating Generally, may serve promising inhibiting reducing responses, restoring dysfunction.

Language: Английский

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Fighting age-related orthopedic diseases: focusing on ferroptosis

Bone Research, Journal Year: 2023, Volume and Issue: 11(1)

Published: March 1, 2023

Abstract Ferroptosis, a unique type of cell death, is characterized by iron-dependent accumulation and lipid peroxidation. It closely related to multiple biological processes, including iron metabolism, polyunsaturated fatty acid the biosynthesis compounds with antioxidant activities, glutathione. In past 10 years, increasing evidence has indicated potentially strong relationship between ferroptosis onset progression age-related orthopedic diseases, such as osteoporosis osteoarthritis. Therefore, in-depth knowledge regulatory mechanisms in diseases may help improve disease treatment prevention. This review provides an overview recent research on its influences bone cartilage homeostasis. begins brief systemic metabolism ferroptosis, particularly potential ferroptosis. presents discussion role promotion loss degradation inhibition osteogenesis. Finally, it focuses future targeting treat intention inspiring further clinical development therapeutic strategies.

Language: Английский

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The double-edged functions of necroptosis

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(2)

Published: Feb. 27, 2023

Abstract Necroptosis refers to a regulated form of cell death induced by variety stimuli. Although it has been implicated in the pathogenesis many diseases, there is evidence support that necroptosis not purely detrimental process. We propose “double-edged sword” terms physiology and pathology. On one hand, can trigger an uncontrolled inflammatory cascade response, resulting severe tissue injury, disease chronicity, even tumor progression. other functions as host defense mechanism, exerting antipathogenic antitumor effects through its powerful pro-inflammatory properties. Moreover, plays important role during both development regeneration. Misestimation multifaceted features may influence therapeutic approaches targeting necroptosis. In this review, we summarize current knowledge pathways involved well five steps determine occurrence. The dual physiological pathological conditions also highlighted. Future studies strategies should fully consider complicated properties type death.

Language: Английский

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Single cell RNA-seq analysis identifies ferroptotic chondrocyte cluster and reveals TRPV1 as an anti-ferroptotic target in osteoarthritis

EBioMedicine, Journal Year: 2022, Volume and Issue: 84, P. 104258 - 104258

Published: Sept. 19, 2022

Language: Английский

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Evidence of pyroptosis and ferroptosis extensively involved in autoimmune diseases at the single-cell transcriptome level

Journal of Translational Medicine, Journal Year: 2022, Volume and Issue: 20(1)

Published: Aug. 12, 2022

Approximately 8-9% of the world's population is affected by autoimmune diseases, and yet mechanism autoimmunity trigger largely understudied. Two unique cell death modalities, ferroptosis pyroptosis, provide a new perspective on mechanisms leading to development treatment strategies.Using scRNA-seq datasets, aberrant trend pyroptosis-related genes were analyzed in several representative diseases (psoriasis, atopic dermatitis, vitiligo, multiple sclerosis, systemic sclerosis-associated interstitial lung disease, Crohn's experimental orchitis). Cell line models also assessed using bulk RNA-seq qPCR.A substantial difference was observed between normal disease samples involving pyroptosis. In present study, pyroptosis showed an imbalance different keratinocyte lineages psoriatic skinin addition pyroptosis-sensitive subset dermatitis (AD) skin. The results revealed that are involved epidermal melanocyte destruction vitiligo. Aberrant has been detected orchitis. adopted study identified pro-inflammatory factors can drive changes pyroptosis.These involvement pathological process at level. IFN-γ critical inducer sensitivity, two models.

Language: Английский

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Periodontal microbiology and microbial etiology of periodontal diseases: Historical concepts and contemporary perspectives

Periodontology 2000, Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 20, 2023

Abstract This narrative review summarizes the collective knowledge on periodontal microbiology, through a historical timeline that highlights European contribution in global field. The etiological concepts disease culminate to ecological plaque hypothesis and its dysbiosis‐centered interpretation. Reference is made anerobic microbiology discovery of select pathogens their virulence factors, as well biofilms. evolution contemporary molecular methods high‐throughput platforms highlighted appreciating breadth depth microbiome. Finally clinical brought into perspective with different microbial species diagnosis, combination host biomarkers for this purpose, use antimicrobials treatment disease.

Language: Английский

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Lipid peroxidation in osteoarthritis: focusing on 4-hydroxynonenal, malondialdehyde, and ferroptosis

Cell Death Discovery, Journal Year: 2023, Volume and Issue: 9(1)

Published: Aug. 29, 2023

Abstract Osteoarthritis (OA) is a multifactorial and increasingly prevalent degenerative disease that affects the whole joint. The pathogenesis of OA poorly understood there lack therapeutic interventions to reverse pathological process this disease. Accumulating studies have shown overproduction reactive oxygen species (ROS) ROS-induced lipid peroxidation are involved in OA. 4-Hydroxy-2-nonenal (4-HNE) malondialdehyde (MDA) received considerable attention for their role cartilage degeneration subchondral bone remodeling during development. Ferroptosis form cell death characterized by control membrane recent suggested chondrocyte ferroptosis contributes progression. In review, we aim discuss peroxidation-derived 4-HNE MDA progression addition, potential controlling accumulation inhibiting discussed.

Language: Английский

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The gut microbiota metabolite capsiate regulate SLC2A1 expression by targeting HIF‐1α to inhibit knee osteoarthritis‐induced ferroptosis

Aging Cell, Journal Year: 2023, Volume and Issue: 22(6)

Published: March 8, 2023

Abstract Ferroptosis is an iron‐dependent cell death that has been found to aggravate the progression of osteoarthritis (OA) and gut microbiota‐ OA axis refers bidirectional information network between microbiota OA, which may provide a new way protect OA. However, role microbiota‐derived metabolites in ferroptosis‐relative remains unclear. The objective this study was analyze protective effect its metabolite capsiate (CAT) on vivo vitro experiments. From June 2021 February 2022, 78 patients were evaluated retrospectively divided into two groups: health group ( n = 39) 40). Iron oxidative stress indicators determined peripheral blood samples. And then experiments, surgically destabilized medial meniscus (DMM) mice model established treated with CAT or Ferric Inhibitor‐1 (Fer‐1). Solute Carrier Family 2 Member 1 (SLC2A1) short hairpin RNA (shRNA) utilized inhibit SLC2A1 expression. Serum iron increased significantly but total binding capacity decreased than healthy people p < 0.0001). least absolute shrinkage selection operator clinical prediction suggested serum iron, capacity, transferrin, superoxide dismutase all independent predictors 0.001). Bioinformatics results SLC2A1, Metastasis‐Associated Lung Adenocarcinoma Transcript (MALAT1), HIF‐1α (Hypoxia Inducible Factor Alpha)‐related signaling pathways play important homeostasis In addition, 16s sequencing untargeted metabolomics used find negatively correlated Osteoarthritis Research Society International (OARSI) scores for chondrogenic degeneration 0.0017). Moreover, reduced ferroptosis‐dependent vitro. against could be eliminated by silencing SLC2A1. upregulated levels DMM group. HIF‐1α, MALAT1, apoptosis after knockout chondrocyte cells Finally, downregulation expression Adeno‐associated Virus (AAV) ‐SLC2A1 shRNA improves vivo. Our findings indicated inhibited HIF‐1a activating

Language: Английский

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