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International Journal of Molecular... Dec 2023The objective of this review is to systematically analyze the potential correlation between gut microbiota and osteoarthritis (OA) as well as to evaluate the feasibility... (Review)
Review
The objective of this review is to systematically analyze the potential correlation between gut microbiota and osteoarthritis (OA) as well as to evaluate the feasibility of microbiota-targeted therapies for treating OA. Studies conducted from October 2013 to October 2023 were identified via a search on electronic databases such as PubMed, Web of Science, and Scopus, following established PRISMA statement standards. Two reviewers independently screened, assessed, and extracted relevant data, and then they graded the studies using the ROBINS I tool for non-randomized interventions studies and SYRCLE's risk-of-bias tool for animal studies. A search through 370 studies yielded 38 studies (24 preclinical and 14 clinical) that were included. In vivo research has predominantly concentrated on modifying the gut microbiota microenvironment, using dietary supplements, probiotics, and prebiotics to modify the OA status. are the most thoroughly examined with found to effectively reduce cartilage damage, inflammatory factors, and pain. Additionally, inhibits the development of OA by preventing high-fat diet (HFD)-induced obesity and protecting cartilage from damage. Although there are limited clinical studies, certain compositions of intestinal microbiota may be associated with onset and progression of OA, while others are linked to pain reduction in OA patients. Based on preclinical studies, there is evidence to suggest that the gut microbiota could play a significant role in the development and progression of OA. However, due to the scarcity of clinical studies, the exact mechanism linking the gut microbiota and OA remains unclear. Further research is necessary to evaluate specific gut microbiota compositions, potential pathogens, and their corresponding signaling pathways that contribute to the onset and progression of OA. This will help to validate the potential of targeting gut microbiota for treating OA patients.
Topics: Animals; Humans; Gastrointestinal Microbiome; Osteoarthritis; Microbiota; Databases, Factual; Lactobacillus; Pain
PubMed: 38203314
DOI: 10.3390/ijms25010143 -
Systematic Reviews Mar 2024Manual therapy (MT) is frequently used in combination with management of osteoarthritis of the knee, but there is no consensus on the exact efficacy of this treatment... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Manual therapy (MT) is frequently used in combination with management of osteoarthritis of the knee, but there is no consensus on the exact efficacy of this treatment strategy. The purpose of this systematic review and meta-analysis was to evaluate the pain relief and safety of MT for treatment of knee osteoarthritis (KOA).
METHODS
Randomized controlled trials evaluating MT in patients with KOA in major English and Chinese journals were searched in the following databases: Wanfang, China Science and Technology Journal Database (VIP database), China National Knowledge Infrastructure (CNKI), PubMed, Embase, Web of Science, and the Cochrane Library databases through June 2023. The methodological quality and quality of evidence of the included studies were assessed using Cochrane's risk-of-bias 2 (ROB 2) tool and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool. Data analysis was performed using Stata version 15.0 software. After use of Galbraith plots to exclude studies that could lead to heterogeneity, random effects models were used to analyze the remaining data and test the consistency of the findings. We used meta-regression to assess the effect of treatment period, patient age, and sex ratio on outcomes. Funnel plots and Egger's test were used to evaluate publication bias. Sensitivity analyses were used to determine the reliability of the results.
RESULTS
A total of 25 studies, with 2376 participants, were included in this review. The overall methodological quality of the included studies was limited. Our findings suggest that MT has a positive impact on pain relief outcomes in KOA patients. The meta-analysis showed that MT was superior to usual care (SMD = 2.04, 95% CI 0.94, 3.14, I = 96.3%; low evidence quality) and exercise (SMD = 1.56, 95% CI 0.41, 2.71, I = 96.3%; low evidence quality) for reducing pain. In terms of improvement in visual analogue scale (VAS) scores, MT treatment beyond 4 weeks (SMD = 1.56, 95% CI 0.41, 2.71, I = 96.3%) may be superior to treatments less than or equal to 4 weeks (SMD = 1.24, 95% CI 0.56, 1.95, I = 94.7%). No serious adverse events associated with MT were reported.
CONCLUSIONS
MT may be effective at reducing pain in patients with KOA and may be more effective after a 4-week treatment period. Compared with usual care and exercise therapy, MT may be superior at reducing KOA pain in the short term (9 weeks), but its long-term efficacy requires careful consideration of evidence-based outcomes. MT appears to be safe for KOA patients, though clinicians should inform patients of the potential risk of MT-related adverse events.
Topics: Humans; Osteoarthritis, Knee; Reproducibility of Results; Pain; Pain Management; Musculoskeletal Manipulations
PubMed: 38504373
DOI: 10.1186/s13643-024-02467-7 -
Advanced Science (Weinheim,... Apr 2024Osteoarthritis (OA) is the most common degenerative joint disease worldwide, with the main pathological manifestation of articular cartilage degeneration. It have been...
Osteoarthritis (OA) is the most common degenerative joint disease worldwide, with the main pathological manifestation of articular cartilage degeneration. It have been investigated that pharmacological activation of transient receptor potential vanilloid 1 (TRPV1) significantly alleviated cartilage degeneration by abolishing chondrocyte ferroptosis. In this work, in view of the thermal activated feature of TRPV1, Citrate-stabilized gold nanorods (Cit-AuNRs) is conjugated to TRPV1 monoclonal antibody (Cit-AuNRs@Anti-TRPV1) as a photothermal switch for TRPV1 activation in chondrocytes under near infrared (NIR) irradiation. The conjugation of TRPV1 monoclonal antibody barely affect the morphology and physicochemical properties of Cit-AuNRs. Under NIR irradiation, Cit-AuNRs@Anti-TRPV1 exhibited good biocompatibility and flexible photothermal responsiveness. Intra-articular injection of Cit-AuNRs@Anti-TRPV1 followed by NIR irradiation significantly activated TRPV1 and attenuated cartilage degradation by suppressing chondrocytes ferroptosis. The osteophyte formation and subchondral bone sclerosis are remarkably alleviated by NIR-inspired Cit-AuNRs@Anti-TRPV1. Furthermore, the activation of TRPV1 by Cit-AuNRs@Anti-TRPV1 evidently improved physical activities and alleviated pain of destabilization of the medial meniscus (DMM)-induced OA mice. The study reveals Cit-AuNRs@Anti-TRPV1 under NIR irradiation protects chondrocytes from ferroptosis and attenuates OA progression, providing a potential therapeutic strategy for the treatment of OA.
Topics: Animals; Male; Mice; Chondrocytes; Disease Models, Animal; Disease Progression; Gold; Infrared Rays; Mice, Inbred C57BL; Nanotubes; Osteoarthritis; TRPV Cation Channels
PubMed: 38358041
DOI: 10.1002/advs.202307683 -
Advanced Science (Weinheim,... May 2024Efferocytosis, an intrinsic regulatory mechanism to eliminate apoptotic cells, will be suppressed due to the delayed apoptosis process in aging-related diseases, such as...
Efferocytosis, an intrinsic regulatory mechanism to eliminate apoptotic cells, will be suppressed due to the delayed apoptosis process in aging-related diseases, such as osteoarthritis (OA). In this study, cartilage lesion-localized hydrogel microspheres are developed to remodel the in situ efferocytosis to reverse cartilage senescence and recruit endogenous stem cells to accelerate cartilage repair. Specifically, aldehyde- and methacrylic anhydride (MA)-modified hyaluronic acid hydrogel microspheres (AHM), loaded with pro-apoptotic liposomes (liposomes encapsulating ABT263, A-Lipo) and PDGF-BB, namely A-Lipo/PAHM, are prepared by microfluidic and photo-cross-linking techniques. By a degraded porcine cartilage explant OA model, the in situ cartilage lesion location experiment illustrated that aldehyde-functionalized microspheres promote affinity for degraded cartilage. In vitro data showed that A-Lipo induced apoptosis of senescent chondrocytes (Sn-chondrocytes), which can then be phagocytosed by the efferocytosis of macrophages, and remodeling efferocytosis facilitated the protection of normal chondrocytes and maintained the chondrogenic differentiation capacity of MSCs. In vivo experiments confirmed that hydrogel microspheres localized to cartilage lesion reversed cartilage senescence and promoted cartilage repair in OA. It is believed this in situ efferocytosis remodeling strategy can be of great significance for tissue regeneration in aging-related diseases.
Topics: Animals; Microspheres; Swine; Osteoarthritis; Cellular Senescence; Chondrocytes; Disease Models, Animal; Apoptosis; Hydrogels; Cartilage, Articular; Cartilage; Hyaluronic Acid; Efferocytosis
PubMed: 38477444
DOI: 10.1002/advs.202400345 -
Scientific Reports Dec 2023Growth differentiation factor 5 (GDF5), a BMP family member, is highly expressed in the surface layer of articular cartilage. The GDF5 gene is a key risk locus for...
Growth differentiation factor 5 (GDF5), a BMP family member, is highly expressed in the surface layer of articular cartilage. The GDF5 gene is a key risk locus for osteoarthritis and Gdf5-deficient mice show abnormal joint development, indicating that GDF5 is essential in joint development and homeostasis. In this study, we aimed to identify transcription factors involved in Gdf5 expression by performing two-step screening. We first performed microarray analyses to find transcription factors specifically and highly expressed in the superficial zone (SFZ) cells of articular cartilage, and isolated 11 transcription factors highly expressed in SFZ cells but not in costal chondrocytes. To further proceed with the identification, we generated Gdf5-HiBiT knock-in (Gdf5-HiBiT KI) mice, by which we can easily and reproducibly monitor Gdf5 expression, using CRISPR/Cas9 genome editing. Among the 11 transcription factors, Hoxa10 clearly upregulated HiBiT activity in the SFZ cells isolated from Gdf5-HiBiT KI mice. Hoxa10 overexpression increased Gdf5 expression while Hoxa10 knockdown decreased it in the SFZ cells. Moreover, ChIP and promoter assays proved the direct regulation of Gdf5 expression by HOXA10. Thus, our results indicate the important role played by HOXA10 in Gdf5 regulation and the usefulness of Gdf5-HiBiT KI mice for monitoring Gdf5 expression.
Topics: Animals; Mice; Cartilage, Articular; Chondrocytes; Growth Differentiation Factor 5; Osteoarthritis; Transcription Factors
PubMed: 38123662
DOI: 10.1038/s41598-023-50318-7 -
Biomolecules Mar 2024Osteoarthritis (OA) is a common degenerative disease. Although some biomarkers and drug targets of OA have been discovered and employed, limitations and challenges still...
Osteoarthritis (OA) is a common degenerative disease. Although some biomarkers and drug targets of OA have been discovered and employed, limitations and challenges still exist in the targeted therapy of OA. Mendelian randomization (MR) analysis has been regarded as a reliable analytic method to identify effective therapeutic targets. Thus, we aimed to identify novel therapeutic targets for OA and investigate their potential side effects based on MR analysis. In this study, two-sample MR, colocalization analysis, summary-data-based Mendelian randomization (SMR) and Mendelian randomization phenome-wide association study (MR-PheWAS) were conducted. We firstly analyzed data from 4907 plasma proteins to identify potential therapeutic targets associated with OA. In addition, blood expression quantitative trait loci (eQTLs) data sources were used to perform additional validation. A protein-protein interaction (PPI) network was also constructed to delve into the interactions among identified proteins. Then, MR-PheWASs were utilized to assess the potential side effects of core therapeutic targets. After MR analysis and FDR correction, we identified twelve proteins as potential therapeutic targets for knee OA or hip OA. Colocalization analysis and additional validation supported our findings, and PPI networks revealed the interactions among identified proteins. Finally, we identified MAPK3 (OR = 0.855, 95% CI: 0.791-0.923, = 6.88 × 10) and GZMK (OR = 1.278, 95% CI: 1.131-1.444, = 8.58 × 10) as the core therapeutic targets for knee OA, and ITIH1 (OR = 0.847, 95% CI: 0.784-0.915, = 2.44 × 10) for hip OA. A further MR phenome-wide association study revealed the potential side effects of treatments targeting MAPK3, GZMK, and ITIH1. This comprehensive study indicates twelve plasma proteins with potential roles in knee and hip OA as therapeutic targets. This advancement holds promise for the progression of OA drug development, and paves the way for more efficacious treatments of OA.
Topics: Humans; Osteoarthritis, Hip; Proteome; Mendelian Randomization Analysis; Knee Joint; Osteoarthritis, Knee; Blood Proteins; Polymorphism, Single Nucleotide
PubMed: 38540773
DOI: 10.3390/biom14030355 -
Nano Letters Dec 2023The histone deacetylase inhibitor (HDACi) was a milestone in the treatment of refractory T-cell lymphoma. However, the beneficial effects of HDACi have not been...
The histone deacetylase inhibitor (HDACi) was a milestone in the treatment of refractory T-cell lymphoma. However, the beneficial effects of HDACi have not been appreciated in osteoarthritis (OA). Herein, we implemented a microcarrier system because of the outstanding advantages of controlled and sustained release, biodegradability, and biocompatibility. The poly(d,l-lactide--glycolide) (PLGA) microcapsules have a regulated and sustained release profile with a reduced initial burst release, which can improve the encapsulation efficiency of the Chidamide. The emulsion solvent evaporation strategy was used to encapsulate Chidamide in PLGA microcapsules. The encapsulation of Chidamide was established by UV-vis spectra and scanning electron microscopy. Additionally, the inhibition of Tnnt3 and immune stimulation by Chidamide helped to inhibit cartilage destruction and prevent articular cartilage degeneration. Based on the results, the Chidamide in PLGA microcapsules provides a transformative therapeutic strategy for the treatment of osteoarthritis patients to relieve symptoms and protect against cartilage degeneration.
Topics: Humans; Histone Deacetylase Inhibitors; Delayed-Action Preparations; Capsules; Osteoarthritis
PubMed: 38009465
DOI: 10.1021/acs.nanolett.3c03037 -
BMC Medical Genomics Oct 2023Growing evidence supports an association between physical activity (PA) and the risk of osteoarthritis (OA), but this may be influenced by confounding and reverse...
BACKGROUND
Growing evidence supports an association between physical activity (PA) and the risk of osteoarthritis (OA), but this may be influenced by confounding and reverse causality. Therefore, we performed a two-sample Mendelian randomization (MR) analysis to reveal the causal relationship between PA and OA.
METHODS
MR was performed to explore the causation of PA and OA with genetic variants as instrumental variables. The genetic variants were derived from the summary statistics of a large genome-wide association study meta-analysis based on the European population (n = 661,399), including self-reported leisure screen time (LST) and moderate-to-vigorous physical activity (MVPA), and Arthritis Research UK Osteoarthritis Genetics Consortium cohorts (417,596, 393,873 and 403,124 for overall, hip and knee OA, respectively). The major MR analysis used in this work was the inverse variance weighted (IVW) approach, and sensitivity, pleiotropy, and heterogeneity studies were performed to evaluate the validity of the findings.
RESULTS
IVW estimates indicated that LST had a risk effect on overall OA (odds ratio (OR) = 1.309, 95% confidence interval (CI): 1.198-1.430, P = 2.330 × 10), hip OA (OR = 1.132, 95% CI: 1.009-1.269, P = 0.034) and knee OA (OR = 1.435. 95% CI: 1.286-1.602, P = 1.225 × 10). In contrast, no causal relationship was found between MVPA and OA (overall OA: OR = 0.895, 95% CI: 0.664-1.205, P = 0.465; hip OA: OR = 1.189, 95% CI: 0.792-1.786, P = 0.404; knee OA: OR = 0.707, 95% CI: 0.490 -1.021, P = 0.064). In addition, we observed significant heterogeneity in instrumental variables, but no horizontal pleiotropy was detected.
CONCLUSIONS
Recent findings demonstrated a protective impact of reducing LST on OA, independent of MVPA. This provides valuable insights into the role of physical activity in OA and offers lifestyle recommendations, such as reducing recreational sedentary behaviors and promoting appropriate exercise, for individuals at risk of OA.
Topics: Humans; Exercise; Genome-Wide Association Study; Mendelian Randomization Analysis; Osteoarthritis, Hip; Osteoarthritis, Knee; Polymorphism, Single Nucleotide
PubMed: 37814247
DOI: 10.1186/s12920-023-01681-x -
Frontiers in Immunology 2024Osteoarthritis (OA) is associated with excessive cartilage degradation, inflammation, and decreased autophagy. Insufficient efficacy of conventional monotherapies and...
INTRODUCTION
Osteoarthritis (OA) is associated with excessive cartilage degradation, inflammation, and decreased autophagy. Insufficient efficacy of conventional monotherapies and poor tissue regeneration due to side effects are just some of the unresolved issues. Our previous research has shown that Calebin A (CA), a component of turmeric (), has pronounced anti-inflammatory and anti-oxidative effects by modulating various cell signaling pathways. Whether CA protects chondrocytes from degradation and apoptosis in the OA environment (EN), particularly the autophagy signaling pathway, is however completely unclear.
METHODS
To study the anti-degradative and anti-apoptotic effects of CA in an inflamed joint, an model of OA-EN was created and treated with antisense oligonucleotides targeting NF-κB (ASO-NF-κB), and IκB kinase (IKK) inhibitor (BMS-345541) or the autophagy inhibitor 3-methyladenine (3-MA) and/or CA to affect chondrocyte proliferation, degradation, apoptosis, and autophagy. The mechanisms underlying the CA effects were investigated by MTT assays, immunofluorescence, transmission electron microscopy, and Western blot analysis in a 3D-OA high-density culture model.
RESULTS
In contrast to OA-EN or TNF-α-EN, a treatment with CA protects chondrocytes from stress-induced defects by inhibiting apoptosis, matrix degradation, and signaling pathways associated with inflammation (NF-κB, MMP9) or autophagy-repression (mTOR/PI3K/Akt), while promoting the expression of matrix compounds (collagen II, cartilage specific proteoglycans), transcription factor Sox9, and autophagy-associated proteins (Beclin-1, LC3). However, the preventive properties of CA in OA-EN could be partially abrogated by the autophagy inhibitor 3-MA.
DISCUSSION
The present results reveal for the first time that CA is able to ameliorate the progression of OA by modulating autophagy pathway, inhibiting inflammation and apoptosis in chondrocytes, suggesting that CA may be a novel therapeutic compound for OA.
Topics: Humans; NF-kappa B; Phosphatidylinositol 3-Kinases; Osteoarthritis; Inflammation; Autophagy
PubMed: 38500879
DOI: 10.3389/fimmu.2024.1363947 -
Clinical and Translational Medicine Sep 2023Osteoarthritis (OA) is a prevalent and debilitating condition, that is, directly associated with cholesterol metabolism. Nevertheless, the molecular mechanisms of OA...
BACKGROUND
Osteoarthritis (OA) is a prevalent and debilitating condition, that is, directly associated with cholesterol metabolism. Nevertheless, the molecular mechanisms of OA remain largely unknown, and the role of cholesterol in this process has not been thoroughly investigated. This study aimed to investigate the role of a novel circular RNA, circARPC1B in the relationship between cholesterol and OA progression.
METHODS
We measured total cholesterol (TC) levels in the synovial fluid of patients with or without OA to determine the diagnostic role of cholesterol in OA. The effects of cholesterol were explored in human and mouse chondrocytes in vitro. An in vivo OA model was also established in mice fed a high-cholesterol diet (HCD) to explore the role of cholesterol in OA. RNAseq analysis was used to study the influence of cholesterol on circRNAs in chondrocytes. The role of circARPC1B in the OA development was verified through circARPC1B overexpression and knockdown. Additionally, RNA pulldown assays and RNA binding protein immunoprecipitation were used to determine the interaction between circARPC1B and Vimentin. CircARPC1B adeno-associated virus (AAV) was used to determine the role of circARPC1B in cholesterol-induced OA.
RESULTS
TC levels in synovial fluid of OA patients were found to be elevated and exhibited high sensitivity and specificity as predictors of OA diagnosis. Moreover, elevated cholesterol accelerated OA progression. CircARPC1B was downregulated in chondrocytes treated with cholesterol and played a crucial role in preserving the extracellular matrix (ECM). Mechanistically, circARPC1B is competitively bound to the E3 ligase synoviolin 1 (SYVN1) binding site on Vimentin, inhibiting the proteasomal degradation of Vimentin. Furthermore, circARPC1B AAV infection alleviates Vimentin degradation and OA progression caused by high cholesterol.
CONCLUSIONS
These findings indicate that the cholesterol-circARPC1B-Vimentin axis plays a crucial role in OA progression, and circARPC1B gene therapy has the opportunity to provide a potential therapeutic approach for OA.
Topics: Humans; Mice; Animals; Cartilage, Articular; RNA, Circular; MicroRNAs; Hypercholesterolemia; Vimentin; Osteoarthritis; Cholesterol
PubMed: 37740460
DOI: 10.1002/ctm2.1415