Search Results (1,532)

Osteoarthritis (OA) is a common, disabling joint disease characterized by complex inflammatory, oxidative, and catabolic cascades that culminate in progressive cartilage degradation, subchondral bone remodeling, and synovitis. Standard pharmacological treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs) provide symptomatic relief of pain but do not prevent the progression of the disease and are often associated with serious gastrointestinal, renal and cardiovascular side effects following long-term use. Epigallocatechin-3-gallate (EGCG), resveratrol, curcumin, quercetin, luteolin and genistein are naturally occurring polyphenols which have been identified as promising disease-modifying osteoarthritis drugs (DMOADs). Mechanistically, these phytochemicals suppress key pro-inflammatory signaling pathways (NF-κB, MAPK), downregulate matrix-degrading enzymes (MMP-13, ADAMTS-5), mitigate reactive oxygen species (ROS), and attenuate chondrocyte apoptosis and senescence. Polyphenols have been shown in pre-clinical and clinical trials to reduce joint pain and preserve cartilage integrity. They also have a synergistic effect with conventional drugs, resulting in lower doses and reduced toxicity. However, their clinical translation has been hampered by poor oral bioavailability, rapid Phase II metabolism, and short intra-articular retention. Advanced drug-delivery systems, such as nanoparticles, liposomes, and sustained-release hydrogels, are essential to overcome these pharmacokinetic bottlenecks and realize their full therapeutic potential in OA management. Full article

Achondroplasia (ACH) is the most common non-lethal skeletal dysplasia and is caused in the vast majority of cases by a heterozygous gain-of-function variant in fibroblast growth factor receptor 3 (FGFR3, p.Gly380Arg). Hyperactive FGFR3 signaling constrains endochondral bone growth by suppressing growth-plate chondrocyte proliferation and hypertrophic differentiation. In the past decade, management has expanded beyond supportive care, and several mechanism-based interventions have shown disease-modifying effects in clinical studies. These include the activation of the NPR2/CNP axis with vosoritide and navepegritide and the pharmacologic attenuation of FGFR signaling with infigratinib, while extracellular biologics designed to modulate ligand–receptor interactions remain investigational. In parallel, gene-based approaches are increasingly discussed as routes toward the etiology-directed control of the causal driver, ranging from the cartilage-biased tuning of FGFR3 expression to variant-level genome editing concepts. Here, we synthesize the current therapeutic landscape, explicitly distinguish pathway-targeted disease modification from etiology-directed genetic strategies, and highlight the key translational barriers for gene-based approaches, including target-tissue delivery to the growth-plate, dose control and durability across development, redosing and immunogenicity constraints, and long-term safety. Full article

Chronic musculoskeletal disorders, including osteoarthritis, rheumatoid arthritis, and tendinopathies, converge on persistent synovial inflammation, matrix catabolism, and impaired repair. This review synthesizes molecular evidence that the cholinergic anti-inflammatory pathway (CAP), the efferent vagal arm of the inflammatory reflex, behaves as a rheostat of the musculoskeletal microenvironment. Activation of the α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages, chondrocytes, osteoblasts, and synoviocytes suppresses nuclear factor-κB (NF-κB) and NLRP3 inflammasome signaling, downregulates MMP-1, MMP-3, and MMP-13, and reduces osteoblast RANKL production; effects on OPG and on the RANKL/OPG ratio under vagal stimulation remain uncharacterized, while favoring a pro-resolution M2-like macrophage program; context-dependent pro-inflammatory responses have also been reported. Bidirectional CAP and mesenchymal stromal cell (MSC) crosstalk indicates that MSCs both sense cholinergic cues and require an intact vagal arc for full immunomodulation. Along the gut–vagus–joint axis, dysbiosis and endotoxin translocation attenuate vagal signaling and amplify systemic inflammatory tone. Because orthobiologics such as platelet-rich plasma, bone marrow aspirate concentrate, and MSCs act within this milieu, cholinergic tone appears associated with the terrain that conditions their efficacy. Heart rate variability stratification and vagal neuromodulation may represent testable adjuncts, although prospective validation in orthobiologic populations remains absent. Preclinical and early clinical evidence is critically appraised throughout. Full article

Background/Objective: Osteoarthritis lacks disease-modifying therapy, and NF-κB signaling is among the best-supported intervention points in cartilage. Sinomenine suppresses this pathway in chondrocytes, but only its downstream consequences are known, and network pharmacology rarely measures its own accuracy. Methods: Targets from six prediction resources were intersected with osteoarthritis genes from five databases and with cartilage and synovial differentially expressed genes. Candidates underwent topological analysis and unrestricted enrichment; prioritized targets were examined by docking and triplicate 100 ns molecular dynamics. Benchmarking used a curated bioactivity reference set, with a variant correcting input-validation overlap. Predictions were tested by thermal shift, limited proteolysis, NMR, thermophoresis, and kinase and silencing assays in interleukin-1β-challenged chondrocytes and in mice after medial meniscus destabilization. Results: Integration yielded 96 candidates, 34 transcriptionally corroborated, giving a network of 78 nodes and 241 edges with 12 consensus hubs. NF-κB signaling ranked first among 74 enriched pathways (adjusted p = 2.7 × 10⁻²⁰), and convergent criteria prioritized IKBKB, RELA, TNF, PTGS2 and MMP9. Benchmarking gave an area under the curve that fell from 0.81 to 0.74 and sensitivity from 0.73 to 0.57 after correcting for circularity. Sinomenine raised the melting temperature of IKBKB by 4.3 °C, bound it at 8.7 μM and inhibited it ATP-competitively, whereas RELA and CHUK showed no engagement. Nuclear p65 fell from 71.3% to 34.8%, IKBKB silencing abolished most of the MMP13 response, and cartilage damage scores fell from 5.0 to 2.5 at 40 mg/kg. Conclusions: Sinomenine engages IKBKB directly and acts principally at the IKK-dependent activation step. The generating pipeline proved only moderately accurate once circularity was corrected, which argues for reporting such metrics routinely. Full article

Osteoarthritis (OA) is a chronic progressive joint disease characterized by articular cartilage degeneration, subchondral bone remodeling, osteophyte formation, and synovitis. It is one of the most common disabling diseases in the middle-aged and elderly population. At present, clinical treatment is mainly based on relieving symptoms, and there is still a lack of interventions that can prevent or reverse the disease process. In recent years, bioactive components derived from medicine–food homology (MFH) and Medicinal Health Food (MHF) have received extensive attention in the prevention and treatment of osteoarthritis due to their high safety and multi-target effects. In this paper, bioactive components with anti-osteoarthritis effects in medicinal and edible homologous and medicinal health foods are systematically reviewed, including polyphenols, flavonoids, terpenoids, alkaloids, and polysaccharides. The progress of research into cartilage protection through the regulation of inflammatory signaling pathways, mitigation of oxidative stress, regulation of chondrocyte metabolism, and epigenetic modification is summarized, and the future research directions in this field are discussed. Full article

Oxidative stress and persistent inflammation are central mechanisms in osteoarthritis (OA), contributing to chondrocyte dysfunction, mitochondrial impairment, extracellular matrix degradation, pain-related signaling, and progressive joint tissue remodeling. Reactive oxygen species (ROS) act not only as damaging agents but also as regulators of redox-sensitive inflammatory pathways, including NF-κB, MAPK, and Nrf2-related antioxidant responses. Accordingly, localized strategies capable of modulating the oxidative–inflammatory microenvironment may offer therapeutic advantages over non-targeted antioxidant approaches. This review summarizes current evidence on natural hydrogel-based systems containing propolis and honey as potential redox-modulating and anti-inflammatory platforms for OA-related tissue degeneration. Propolis and honey are bee-derived bioactive products rich in polyphenols and other redox-active compounds with antioxidant, anti-inflammatory, antimicrobial, and tissue-protective properties. Their incorporation into hydrogel matrices may support sustained local delivery, improved tissue retention, and stimulus-responsive release within inflamed or oxidatively stressed tissues. Particular attention is given to mechanisms involving ROS regulation, suppression of inflammatory mediators, activation of endogenous antioxidant defenses, and protection of cartilage extracellular matrix. Current formulation evidence is also critically interpreted according to its disease specificity, distinguishing direct OA/cartilage-related evidence from indirect wound healing and tissue repair data. The review also addresses intra-articular biomechanical requirements, enzyme-responsive degradation, immunological safety, formulation standardization, and translational barriers. Full article

Background: Osteoarthritis (OA) is a prevalent degenerative joint disease lacking effective disease-modifying therapies, which necessitates the discovery of key genes for mechanistic exploration and therapeutic development. Methods: We integrated three large-scale cis-protein quantitative trait locus datasets and two OA genome-wide association study summary statistics to screen candidate proteins by two-stage proteome-wide Mendelian randomization (MR). Causal association reliability was validated via summary-data-based Mendelian randomization (SMR) and Bayesian colocalization analyses. A phenome-wide association study (PheWAS) was performed to evaluate potential pleiotropic effects of the candidates. Subsequently, transcriptomic and single-cell RNA sequencing datasets were employed to evaluate the candidate genes’ expression stability, classification efficacy in the in vitro models of OA, cell-specific enrichment, and pseudotime expression dynamics in cartilage. Finally, drug repurposing potential was explored by integrating drug–gene interaction database searches and molecular docking. Results: Two-stage cis-pQTL MR combined with cis-eQTL-based SMR analysis identified 14 plasma proteins with consistent effects at the protein and transcript levels. RNA-seq revealed that adrenomedullin (ADM) and complement factor H (CFH) were upregulated in two in vitro models of OA, and both genes exhibited favorable classification efficacy in these models. Bayesian colocalization analysis provided evidence of shared causal variants for ADM, and PheWAS did not detect significant pleiotropic associations for ADM or CFH across the tested phenotypes. Single-cell analysis indicated that ADM was enriched in pre-fibrocartilage chondrocytes with biphasic pseudotime expression, whereas CFH was widely expressed across chondrocyte subsets. Database screening identified 15 potential drugs for ADM and 6 for CFH. Conclusions: Combining MR, multi-omics and pharmacological evidence, we prioritized ADM and CFH as OA candidate genes. Full article

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) represent a promising cell-free therapeutic strategy for cartilage regeneration and inflammation modulation in degenerative and inflammatory musculoskeletal disorders, including osteoarthritis (OA), rheumatoid arthritis (RA) and intervertebral disc degeneration (IVDD). MSC-EVs enhance cartilage repair by promoting chondrocyte proliferation, migration, survival and extracellular matrix (ECM) synthesis to maintain cartilage homeostasis. In parallel, they exert anti-inflammatory and anti-catabolic effects by suppressing inflammatory cytokines, matrix-degrading enzymes, oxidative stress and inflammasome activation. In OA, MSC-EVs regulate chondrocyte function, ECM remodelling, immune responses and tissue regeneration by modulating multiple signalling pathways, including NF-κB, PI3K/AKT, MAPK, Wnt/β-catenin and YAP signalling. In RA, MSC-EVs orchestrate innate and adaptive immune regulation, metabolic reprogramming and tissue repair pathways. In IVDD, MSC-EVs suppress chronic inflammation, reduce nucleus pulposus cell apoptosis, enhance cell proliferation and promote ECM synthesis, facilitating disc regeneration and functional restoration. Despite their therapeutic potential, several challenges hinder clinical translation. This review summarises current understanding of MSC-EV-mediated mechanisms in OA, RA and IVDD, and proposes strategies to enhance therapeutic efficacy and accelerate clinical application in musculoskeletal regenerative medicine. Full article

Background/Objectives: Osteoarthritis (OA) is strongly associated with mitochondrial dysfunction, oxidative stress, and the accumulation of mitochondrial DNA (mtDNA) alterations in several joint-associated cell types, including chondrocytes, synoviocytes, and mesenchymal stromal cells (MSCs). These alterations contribute to impaired cellular homeostasis and reduced regenerative potential. In this study, we systematically characterized mtDNA heteroplasmy and variant distribution across bone marrow MSCs, induced pluripotent stem cells (iPSCs) and induced MSCs (iMSCs) derived from OA patients and healthy donors. Methods: Ultra-deep mitochondrial genome sequencing was integrated with transcriptomic and miRNome analyses to investigate mitochondrial remodeling during cellular reprogramming, encompassing changes in mtDNA heteroplasmy, variant distribution, mtDNA copy number and associated transcriptomic adaptations of nuclear-encoded mitochondrial pathways. Results: OA-derived MSCs exhibited a markedly increased heteroplasmic burden, followed by decrease in mtDNA copy number and accumulation of non-synonymous variants, particularly within OXPHOS-related genes, including MT-ND1-5, MT-ATP8, MT-CO1, and MT-RNR1/2. Reprogramming into iPSCs and subsequent differentiation into iMSCs were associated with an increase in mtDNA copy number and a progressive reduction in heteroplasmic variants predicted to have pathogenic potential, including m.7913C>T and m.7821G>A, as well as substantial reduction in heteroplasmic variant burden within several mitochondrial genes, suggesting mitochondrial genome remodeling during cellular reprogramming. Multiomic analysis further revealed coordinated deregulation of mitochondrial-associated nuclear genes and ceRNA regulatory networks involving lncRNAs MEG3 and SNHG14, along with multiple mitochondria-related miRNAs. These findings suggest post-transcriptional regulations associated with mitochondrial adaptation in iMSCs Conclusion: Collectively, our findings suggest that cellular reprogramming is associated with mitochondrial genomic reorganization in the donor-matched cell populations examined. These exploratory observations support the utility of iMSCs as a relevant model for studying OA-associated mitochondrial alterations and as a potential tool for regenerative approaches in OA. Full article

Background/Objectives: This study examined whether dexamethasone (Dex) and decanoic acid (DA) exert complementary effects on inflammatory signaling, catabolic gene expression, and peroxisome proliferator-activated receptor gamma (PPARγ) activation in human chondrocytes. Methods: Two donor-specific primary human chondrocyte models, each derived from a single knee donor, were used, in which cells were treated with Dex (≤0.1 µM), DA (≤500 µM), or combinations thereof. Acute Interleukin-1β(IL-1β)-induced PGE₂ release was evaluated in normal donor cells, whereas prolonged transcriptional responses and PPARγ DNA-binding activity were evaluated in OA donor cells. IL-1β-induced prostaglandin E₂ (PGE₂) release was measured by competitive ELISA after 24 h. Glyceraldehyde-3-phosphate dehydrogenase-normalized transcription of Collagen type II alpha 1, Collagen type I alpha 1, Aggrecan, SRY-Box Transcription Factor 9, Runt-Related Transcription Factor 2, and Matrix Metalloproteinase 13 (MMP13) was assessed by qRT-PCR at 7, 10–14, and 20–28 days. In addition, PPARγ DNA-binding activity was measured after 1 week. Interactions were evaluated by Loewe additivity and highest single agent (HSA) analyses. Results: Dex and DA each reduced PGE₂ release, whereas co-treatment increased potency and maximal inhibition, with a Loewe combination index of 0.4 at 1 nM Dex plus 19 µM DA. In the temporal analysis, Dex plus DA showed a positive MMP13 ΔCt difference versus Dex at 10–14 days (2.42 ± 2.14; p = 0.065) and a more consistent difference at 20–28 days (1.11 ± 0.25; p = 0.016). This agreed with fixed-dose HSA findings at 14 and 28 days (ΔHSA ≈ −75 for 0.1 µM Dex plus 100 µM DA versus Dex). Co-treatment was also associated with increased PPARγ activation beyond the HSA reference (ΔHSA ≈ 0.09 for 0.1 µM Dex plus 100–250 µM DA versus Dex). Conclusions: Dex plus DA co-treatment produced complementary effects on acute PGE₂ inhibition, as well as late-onset MMP13 suppression and PPARγ activity in the donor-specific chondrocyte models studied. These hypothesis-generating findings provide an in vitro rationale for future evaluation of this combination as a corticosteroid-sparing strategy. Full article

Background and Objectives: Traditional open anterior cruciate ligament transection (ACLT) surgical models performed through arthrotomy may introduce capsular trauma and postoperative inflammatory responses that can interfere with the interpretation of post-traumatic osteoarthritis (OA). This study aimed to evaluate the feasibility of a minimally invasive, arthroscopic ACLT rabbit model performed entirely under arthroscopic visualization, without arthrotomy, using a 2.4-mm arthroscope and 2.5-mm shaver, and to provide preliminary structural, histological, synovial, and systemic biochemical characterization of the model for future therapeutic testing. Materials and Methods: Bilateral arthroscopic ACLT was performed in three skeletally mature New Zealand rabbits, followed by a supervised 12-week exercise protocol. Joint degeneration was evaluated macroscopically and histopathologically using the standardized Pritzker-Osteoarthritis Research Society International (OARSI) grading system. Collagen matrix remodeling was assessed via Picrosirius Red staining. Local intra-articular catabolism was quantified via Enzyme-Linked Immunosorbent Assay (ELISA) for matrix metallopeptidase 13 (MMP-13) and interleukin-1β (IL-1β) from synovial fluid. Systemic oxidative stress, including lipid peroxidation biomarkers, malondialdehyde (MDA), and nitric oxide (NO), was evaluated in serum. Results: The arthroscopic approach induced osteoarthritic changes, with severity varying across the cohort. Histopathology revealed vertical matrix fissures and disruption of the normal columnar chondrocyte organization, yielding a median comprehensive Pritzker-OARSI score of 6 (range 6–10), with horizontal degradation restricted to stage 2. Synovial fluid analysis demonstrated measurable concentrations of MMP-13 (188.77 ± 93.87 ng/mL) and IL-1β (174.93 ± 95.51 pg/mL). Furthermore, serum oxidative stress parameters at the 12-week endpoint included lipid peroxidation (MDA: 1.01 ± 0.03 nmol/mL) and NO levels (82.72 ± 0.32 µmol/L), presented descriptively in the absence of a comparator group. Conclusions: This study establishes the first multifaceted pathological baseline of a minimally invasive arthroscopic ACLT rabbit model before therapeutic intervention. The arthroscopic ACLT model produced structural cartilage degeneration alongside measurable intra-articular catabolic and systemic oxidative stress changes, establishing a baseline phenotype and a starting point for future therapeutic studies. Full article

Artocarpin is a promising bioactive compound with anti-inflammatory potential; however, its limited aqueous solubility may restrict its direct biological application. Therefore, artocarpin-loaded chitosan microparticles (CSPs/AE) were prepared as a biocompatible carrier to improve artocarpin delivery. This study aimed to evaluate the cytocompatibility, antioxidant activity, and anti-inflammatory effects of CSPs/AE in lipopolysaccharide (LPS)-stimulated chondrocytes. CSPs/AE maintained high cell viability (>80% at 0.125 and 0.5 mg/mL) and showed significantly lower cytotoxicity than free artocarpin. Morphological and DAPI analyses confirmed preserved cellular and nuclear integrity without marked apoptosis. CSPs/AE at 0.25 mg/mL reduced LPS-induced intracellular ROS accumulation by approximately 79% relative to the LPS group. Western blot results demonstrated inhibition of LPS-induced NF-κB phosphorylation, with CSPs/AE at 0.5 mg/mL reducing p-NF-κB expression to approximately 0.66-fold of that observed in the LPS group. CSPs/AE also partially restored aggrecan and collagen II expression without promoting a fibrocartilage, as indicated by unchanged collagen I. These findings indicate that CSPs/AE attenuate oxidative stress and inflammatory signaling while preserving cartilage matrix components, highlighting their potential for cartilage-protective applications. Full article

Introduction: The clinical translation of biomaterial-based strategies for ear reconstruction remains limited by several challenges, including scaffold design, selection of an optimal cell source, and stability of the new cartilage tissue. Most recent studies still rely on animal-derived cells and fail to demonstrate the long-term maintenance of the chondrogenic phenotype. Methods: In this study, we developed an off-the-shelf poly(lactide-b-ethylene glycol) (PLA-PEG) scaffold combined with clinical-grade alginate (Alg) and cellularized with human nasal chondrocytes for auricular cartilage engineering. Cellularized constructs were evaluated using histological and immunofluorescence analyses to assess extracellular matrix production and quality. In parallel, constructs retrieved after 12 weeks of in vivo implantation were mechanically characterized using a UniVert CellScale testing system to determine variations in compressive strength. Finally, the chondrogenic maturation of the new tissue was evaluated through bulk RNA transcriptomic profiling. Results: Histological, immunofluorescence, and transcriptomic analyses demonstrated robust cartilage matrix deposition with improved compressive properties and high expression of chondrogenic markers, such as ACAN, PRG4, and COL2A1. Furthermore, positive staining for the human-specific Ku80 antibody confirmed the presence of cells of human origin in the newly formed tissue after implantation. Conclusions: Overall, this study provides evidence that the combination of a PLA-PEG + Alg scaffold with human nasal septal chondrocytes represents a promising strategy for future reconstructive applications in auricular tissue engineering. Full article

Background/Objectives: X-linked hypophosphatemia (XLH), the most frequent heritable cause of hypophosphatemic rickets, is characterized by impaired linear growth and skeletal deformities, that can lead to disproportionate short stature. Linear growth depends on the coordinated regulation of systemic endocrine signals and local growth plate regulatory mechanisms controlling chondrocyte proliferation, differentiation, and apoptosis. This review critically discusses the molecular processes underlying growth impairment in XLH, with particular emphasis on growth plate dysfunction. Methods: A narrative review of experimental and clinical studies was conducted, focusing on growth plate biology, and on the pathophysiology of XLH. Particular attention was given to the role of systemic phosphate-regulating hormones, local paracrine factors, and intracellular signaling pathways, as well as the effects of current therapeutic strategies on linear growth. Results: Excess fibroblast growth factor 23 (FGF23) in XLH disrupts phosphate homeostasis and vitamin D metabolism, impairing skeletal mineralization and growth plate signaling. Beyond FGF23-related dysregulation, additional FGF23-independent mechanisms directly affect growth plate chondrocyte function and extracellular matrix composition, further contributing to growth plate disorganization. Current therapeutic approaches, including conventional phosphate and active vitamin D supplementation, FGF23 inhibition with human monoclonal antibody, and combination with recombinant human growth hormone, exert heterogeneous effects on linear growth through distinct biological mechanisms. Conclusions: Growth impairment in XLH reflects the combined impact of systemic endocrine dysregulation, and intrinsic growth plate dysfunctions. A better understanding of these mechanisms may facilitate the development of targeted therapeutic strategies, improving growth outcomes in individuals with XLH. Full article

Articular cartilage exists under hypoxic conditions, where hypoxia-inducible factor (HIF)-1α plays a critical role in maintaining its homeostasis. In osteoarthritis (OA), however, this hypoxic environment is disrupted, and decreased HIF-1α expression contributes to disease progression. HIF-prolyl hydroxylase (HIF-PH) inhibitors stabilize HIF-1α and are clinically used to treat renal anemia; therefore, they may also exert therapeutic effects in OA through the same mechanism. However, their effects on articular cartilage remain unclear. In this study, we investigated the effects of Roxadustat, a HIF-PH inhibitor, both in vitro using rat chondrocytes and in vivo using a monosodium iodoacetate (MIA)-induced rat OA model. Roxadustat showed no cytotoxicity and significantly increased the protein expression of HIF-1α, SRY-box transcription factor 9 (SOX9), and Aggrecan in monolayer cultures. In three-dimensional spheroid cultures, Roxadustat enhanced Safranin O staining and extracellular matrix production and significantly upregulated SOX9 and ACAN mRNA expression. Furthermore, intra-articular administration of Roxadustat in the MIA-induced OA model suppressed cartilage degeneration and significantly reduced the Modified Mankin score. These findings demonstrate that Roxadustat promotes anabolic responses in chondrocytes through stabilization of HIF-1α and suppresses cartilage degeneration in OA. Intra-articular administration of HIF-PH inhibitors may represent a novel disease-modifying therapeutic strategy for OA. Full article