Notch signaling plays a fundamental role in the inflammatory response and has been linked to the pathogenesis of osteoarthritis in murine models of the disease and in humans. To address how Notch signaling modifies transcriptomes and cell populations, we examined the effects of NOTCH2 in chondrocytes from mice harboring a NOTCH2 gain-of-function mutation (Notch2tm1.1Ecan) and a conditional NOTCH2 gain-of-function model expressing the NOTCH2 intracellular domain (NICD2) from the Rosa26 locus (R26-NICD2 mice). Bulk RNA-Sequencing (RNA-Seq) of primary epiphyseal cells from both gain-of-function models established increased expression of pathways associated with the phagosome, genes linked to osteoclast activity in rheumatoid arthritis signaling and pulmonary fibrosis signaling. Expression of genes linked to collagen degradation was enhanced in Notch2tm1.1Ecan cells, while genes related to osteoarthritis pathways were increased in NICD2-expressing cells. Single cell (sc)RNA-Seq of cultured Notch2tm1.1Ecan cells revealed clusters of cells related to limb mesenchyme, chondrogenic cells and fibroblasts including articular synovial fibroblasts. Pseudotime trajectory revealed close associations among clusters in control cultures, but the cluster of articular/synovial fibroblasts was disrupted in cells from Notch2tm1.1Ecan mice. ScRNA-Seq showed similarities in the cluster distributions and pseudotime trajectories of NICD2-expressing and control cells, except for altered progression in a cluster of NICD2-expressing cells. In conclusion, NOTCH2 enhances the activity of pathways associated with inflammation in epiphyseal chondrocytes and disrupts the transcriptome profile of articular/synovial fibroblasts.

To investigate the correlation between MRI-based phenotypes (cartilage-meniscus, subchondral bone, and inflammatory) and radiography-based atrophic and hypertrophic phenotypes, aiming to demonstrate MRI's diagnostic capability in identifying complex osteoarthritis phenotypes that radiography cannot fully capture.

This single-center retrospective study examined knee radiographs and MRIs of patients from November 2021 to April 2023 to identify osteoarthritis phenotypes. Radiographs were staged by the Kellgren-Lawrence system, and both modalities were classified into atrophic or hypertrophic phenotypes. MRIs were further classified into three phenotypes: cartilage-meniscus, subchondral bone, and inflammatory. Associations between phenotypes, Kellgren-Lawrence stage, age, and gender were analyzed with Pearson chi-square test and student T-test. Reliability measurements were evaluated using kappa statistic.

A total of 214 knees from 187 individuals (73.3% women, 26.7% men; mean age 57.1 ± 9.1 years) were included. The hypertrophic MRI phenotype was significantly associated with cartilage-meniscus and subchondral bone phenotypes (p < 0.001). Cartilage-meniscus and subchondral bone phenotypes were less prevalent in Kellgren-Lawrence stage 2 than in stages 3 and 4 (p < 0.001 and p = 0.004, respectively). The subchondral bone phenotype was more common in men (p = 0.022), and the cartilage-meniscus phenotype in the elderly (p < 0.001). Radiography and MRI had substantial agreement (Kappa = 0.637, p < 0.001) in diagnosing hypertrophic and atrophic phenotypes.

The hypertrophic phenotype was associated with cartilage-meniscus and subchondral bone phenotypes, with lower prevalences in Kellgren-Lawrence stage 2 knees. MRI offers enhanced phenotypic characterization, which facilitates more precise and individualized management in osteoarthritis care. Despite limitations compared to MRI, radiography remains valuable for the evaluation of hypertrophic and atrophic phenotypes.

This study aimed to evaluate the impact of various dietary interventions on managing osteoarthritis (OA), a condition significantly affecting global health due to joint alterations driven by inflammatory mediators. A systematic review and meta-analysis, adhering to PRISMA guidelines, examined Randomized Controlled Trials (RCTs) investigating dietary interventions in OA. Two reviewers independently conducted study selection, data extraction, and quality assessment. Random effects models calculated standardized mean differences (SMD) and mean differences (MD). Risk of bias was evaluated with the Cochrane Risk of Bias tool (RoB2), and heterogeneity was assessed using I² values. Nine RCTs (898 participants) were identified, assessing various diets: reduced energy (n = 4), Mediterranean (n = 2), low-fat (n = 2), anti-inflammatory (n = 1), low-carbohydrate (n = 1), and plant-based (n = 1). Dietary interventions significantly improved pain (SMD: -0.67; 95% CI: [-1.01, -0.34]; p < 0.0001), and physical function (SMD: -0.62; 95% CI: [-0.94, -0.30]; p = 0.0001) and body weight (MD: -3.18; 95% CI: [-3.52, -2.83], p < 0.0001). Subgroup analyses revealed reduced energy diets improved pain (SMD: -0.85; 95% CI: [-1.15, -0.55], p < 0.0001), physical function (SMD: -0.95; 95% CI: [-1.33, -0.58], p < 0.0001) and body weight (MD: -3.13; 95% CI: [-3.77, -2.49], p < 0.0001). The Mediterranean diet did not significantly impact pain (SMD: -0.27; 95% CI: [-1.14, 0.60], P = 0.54), or physical function (SMD = -0.28; 95% CI: [-0.79, 0.24], p = 0.29). This study emphasizes the significant impact of dietary interventions on pain, physical function, and weight management in people with OA, with reduced energy diets showing the most effectiveness. Specific dietary patterns show promise but require further investigation.

Osteoarthritis (OA) is a common degenerative joint disease that can lead to chronic pain and disability. The pathogenesis of OA involves chronic low-grade inflammation, characterized by the degradation of chondrocytes, inflammation of the synovium, and systemic low-grade inflammation. This inflammatory response accelerates the progression of OA and contributes to pain and functional impairment. Primary cilia play a crucial role in cellular signal transduction and the maintenance of cartilage matrix homeostasis, and their dysfunction is closely linked to inflammatory responses. Given these roles, primary cilia may significantly contribute to the pathogenesis of OA. This review explores inflammation-associated signaling pathways in OA, including NF-κB, MAPK, JAK/STAT, and PI3K/AKT/mTOR signaling. In addition, we place particular emphasis on cilia-mediated inflammatory modulation in OA. Primary cilia mediate chondrocyte responses to mechanical loading and inflammatory cytokines via pathways including NF-κB, MAPK, TRPV4, and Hedgehog signaling. Notably, alterations in the length and incidence of primary cilia in chondrocytes during OA further underscore their potential role in disease pathogenesis. The identification of biomarkers and therapeutic targets related to primary cilia and inflammatory pathways offers new potential for the treatment and management of OA.

Osteoarthritis (OA) is a common degenerative joint disease associated with chronic inflammation. Epimedin C (EpiC), flavonoid from Epimedin, enhances the extracellular matrix (ECM) expression in human chondrocytes in vitro. This study aims to investigate the effects of EpiC on osteoarthritis progress in vivo. OA is induced in Lewis rats by medial meniscus transection and treatment with intra-articular injections of EpiC. EpiC treatment reduces joint swelling and improves hindlimb weight distribution in MMT-induced OA rats. Pathological changes in cartilage are observed and evaluated by the osteoarthritis research society international (OARSI) score and both EpiC groups have lower OARSI scores than the OA group. The EpiC groups also exhibit higher positive expressions of collagen II and aggrecan, and lower MMP13 and ADAMTS5 in the cartilage. RNA-seq suggest that EpiC may attenuate MMT-induced ECM degradation by inhibiting the JAK-STAT pathway. EpiC promotes the gene expressions of Col2a1 and Acan, while inhibiting Mmp13 and Col10a1 in cartilage. EpiC reduces the phosphorylated STAT3 in human chondrocyte pellets stimulated with inflammatory cytokines. In conclusion, EpiC demonstrates potential as an OA therapeutic by reducing pain and ECM degradation through p-STAT3 inhibition.

Background: Besides conventional norms that recognize synovial fluid (SF) as a joint lubricant, nutritional channel, and a diagnostic tool in knee osteoarthritis (kOA), based on the authors previous studies, this study aims to define functional role of SF in kOA. Methods: U937, a monocytic, human myeloid cell line, was induced with progressive grades of kOA SF, and the induction response was assessed on various pro-inflammatory parameters. This 'SF challenge test model' was further extended to determine the impact of SF on U937 differentiation using macrophage-specific markers and associated transcription factor genes. Mitochondrial membrane potential changes in SF-treated cells were evaluated with fluorescent JC-1 probe. Results: a significant increase in nitric oxide, matrix metalloproteinase (MMP) 1, 13, and vascular endothelial growth factor (VEGF)-1 was noted in the induced cells. A marked increase was seen in CD68, CD86, and the transcription factors -activator protein (AP)-1, interferon regulatory factor (IRF)-1, and signal transducer and activator of transcription (STAT)-6 in the SF-treated cells indicating active monocytes to macrophage differentiation. Reduced mitochondrial membrane potential was reflected by a reduced red-to-green ratio in JC-1 staining. Conclusions: these results underline the active role of OA SF in stimulating and maintaining inflammation in joint cells, fostering monocyte differentiation into pro-inflammatory macrophages. The decline in the membrane potential suggestive of additional inflammatory pathway in OA via the release of pro-apoptotic factors and damaged associated molecular patterns (DAMPs) within the cells. Overall, biochemical modulation of SF warrants a potential approach to intervene inflammatory cascade in OA and mitigate its progression.

Knee osteoarthritis significantly impacts mobility and quality of life. This condition is a leading cause of disability in aging populations, with total knee replacement commonly sought in advanced cases. Traditional nonoperative management strategies, including anti-inflammatories, corticosteroid injections, and hyaluronic acid, often provide limited relief, especially in severe cases. Recently, regenerative therapies such as amniotic suspension allografts (ASA) have emerged as promising alternatives due to their anti-inflammatory and regenerative properties, which may counteract the catabolic effects of osteoarthritis. This systematic review evaluated the efficacy and safety of ASA in reducing pain and improving function among knee osteoarthritis patients. Following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines, a comprehensive search of PubMed and Embase databases initially identified 1,733 studies pertaining to ASA, of which 1,575 were screened, and 9 studies ultimately met the inclusion criteria for detailed analysis of ASA in the treatment of knee osteoarthritis. Data extraction and narrative synthesis focused on outcomes such as pain reduction and functional improvement using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), as well as safety profiles. The results demonstrated notable improvements in pain scores following ASA treatment, as shown by studies reporting increases in KOOS pain scores over 6 months, which generally outperformed hyaluronic acid and saline treatments in pain reduction. Similarly, ASA treatment was associated with substantial improvements in physical function outcome scores, enhancing patients' ability to perform daily activities. Patient-reported outcomes also indicated higher quality of life and functional status, with most patients experiencing high levels of satisfaction. Additionally, ASA's safety profile was favorable, with adverse events primarily mild to moderate in nature, including a few transient events such as knee stiffness and myalgias. This systematic review highlights ASA as an effective therapeutic option for knee osteoarthritis, although further studies focusing on long-term radiographic outcomes and mechanisms of action are recommended to fully establish its benefits and optimize treatment protocols.

Metabolic syndrome (MetS) associated with Osteoarthritis (OA) is an increasingly recognised entity. Whilst the degenerative pattern in cuff-tear arthropathy (CTA) has been well documented, the biological processes behind primary shoulder OA and CTA remain less understood. This study investigates transcriptomic differences in these conditions, alongside the impact of MetS in patients undergoing total shoulder replacement. In a multi-centre study, 20 OA patients undergoing total shoulder replacement were included based on specific treatment indications for OA and cuff-tear arthropathy as well as 25 patients undergoing rotator cuff repair (RCR) as a comparator group. Tissues from subchondral bone, capsule (OA and RCR), and synovium were biopsied, and RNA sequencing was performed using Illumina platforms. Differential gene expression was conducted using DESeq2, adjusting for demographic factors, followed by pathway enrichment using the mitch package. Gene expressions in CTA and primary OA was differentially affected. CTA showed mitochondrial dysfunction, GATD3A downregulation, and increased cartilage degradation, while primary OA was marked by upregulated inflammatory and catabolic pathways. The effect of MetS on these pathologies was further shown. MetS further disrupted WNT/β-catenin signalling in CTA, and in OA. Genes such as ACAN, PANX3, CLU, and VAT1L were upregulated, highlighting potential biomarkers for early OA detection. This transcriptomic analysis reveals key differences between end-stage CTA and primary glenohumeral OA. CTA shows heightened metabolic/protein synthesis activity with less immune-driven inflammation. Under MetS, mitochondrial dysfunction (including GATD3A downregulation) and altered Wnt/β-catenin signalling intensify cartilage and bone damage. In contrast, primary OA features strong complement activation, inflammatory gene expression, and collagen remodelling. MetS worsens both conditions via oxidative stress, advanced glycation end products, and ECM disruption-particularly, increased CS/DS degradation. These distinctions support targeted treatments, from antioxidants and Wnt modulators to aggrecanase inhibitors or clusterin augmentation. Addressing specific molecular disruptions, especially those amplified by MetS, may preserve shoulder function, delay surgical intervention, and improve long-term patient outcomes.

Rheumatoid arthritis (RA) is a systemic autoimmune disease that commonly causes pain in joints and the progressive destruction of cartilage and bone, which significantly reduces the quality of life and increases the social burden. However, there is still no cure for RA, so it is highly important to explore additional adjuvant treatment methods. Studies have indicated that malnutrition, changes in intestinal microbiota, and changes in immune status caused by dietary imbalance are directly related to the onset of RA, indicating that dietary intervention may offer a simple, economical, and practical avenue to relieve RA. Therefore, in this review, we discuss the pathogenesis of RA and summarize the influence of different dietary patterns on RA. In particular, we pointed out that high-fat, high-sugar, and high-salt diets contribute to RA progression, whereas the Mediterranean diet (MD) is beneficial for preventing RA. Furthermore, the ingredients of food, such as dietary fiber, probiotics, and vitamins, help reduce the level of inflammation and relieve joint pain, which may play critical roles in the treatment of RA. Therefore, dietary intervention provides a potential effective approach for adjuvant therapy of RA.

How arthritic synovial fibroblasts (SFs) activate cartilage ECM degradation remains unclear. GALNT enzymes initiate O-glycosylation in the Golgi; when relocated to the ER, their activity stimulates ECM degradation. Here, we show that in human rheumatoid and osteoarthritic synovial SFs, GALNTs are relocated to the ER. In an RA mouse model, GALNTs relocation occurs shortly before arthritis symptoms and abates as the animal recovers. An ER GALNTs inhibitor prevents cartilage ECM degradation in vitro and expression of this chimeric protein in SFs results in the protection of cartilage. One of the ER targets of GALNTs is the resident protein Calnexin, which is exported to the cell surface of arthritic SFs. Calnexin participates in matrix degradation by reducing ECM disulfide bonds. Anti-Calnexin antibodies block ECM degradation and protect animals from RA. In sum, ER O-glycosylation is a key switch in arthritic SFs and glycosylated surface Calnexin could be a therapeutic target.

The medial meniscus extrusion (MME) is associated with increased stress on the knee joint, which leads to cartilage degeneration. To evaluate the etiology of knee osteoarthritis, it is extremely important to create animal models of the disease that more closely resemble actual clinical conditions in terms of symptomatology, molecular biology, and histology. This study aimed to create a clinically relevant model of MME in rats.

Behavioral, molecular biological, and histological changes in the newly developed rat MME model were compared with those in sham and medial meniscus transection and medial collateral ligament transection (MMT) models to examine the characteristics of this model.

In the MME rat model, behavioral evaluation shows abnormalities in gait compared with the other 2 groups, and molecular biological evaluation of the infrapatellar synovia of rats shows that gene expression of inflammatory cytokines, matrix-degrading enzymes, and pain-related nerve growth factor was increased compared with the sham group. Furthermore, histological evaluation reveals that cartilage degeneration was the most severe in the MME group.

The newly developed MME model reproduced the characteristic pathology of MME in clinical practice, such as severe pain, inflammation, and rapid progression of osteoarthritis. The MME model, which might more closely mimic human knee osteoarthritis (OA), could be a useful model for elucidating the pathophysiology and considering therapeutic management for knee OA.

Osteoarthritis is a degenerative joint disease that worsens over time, often resulting in chronic pain. Eulophia nuda (Orchidaceae), a medicinal herb widely used by folklore and indigenous healers for treating arthritis but the active ingredients and the molecular mechanisms of action are yet to be explored. The present study systematically investigates the underlying anti-osteoarthritic mechanism of ENE through network pharmacology, molecular dynamics simulation and experimental assays. A comprehensive search on IMPPAT, KNApSAcK and Pubchem databases resulted 26 active compounds from E. nuda, of which 23 passed the drug-likeness criteria. A total of 2344 compound targets, 1370 osteoarthritis targets and 81 overlapping compound-disease targets were identified. The compound-disease target network resulted in five active constituents with degree > 23. Topological analysis of the protein-protein interaction network revealed six hub target genes. KEGG analysis revealed IL-17, TNF and AGE-RAGE signalling pathways as the enriched pathways involved in osteoarthritis. Molecular docking showed eulophiol had the good binding energy (>8.0 kcal/mol) with MMP9, JNK1, p38 and NF-kβ. The molecular dynamics simulations and the MMPBSA analysis indicate high stability and greater binding energy of eulophiol with the target proteins. ENE did not show cytotoxicity on SW982 cells up to a concentration of 100 μg/ml. ENE exhibited considerable anti-inflammatory effect by reducing PGE2, IL-6 and IL8 levels as well as reducing the mRNA expression of matrix metalloproteinases (MMP2 and MMP9). Furthermore, ENE effectively inhibited the NF-kβ nuclear translocation and phosphorylation of ERK2, p38 and JNK in SW982 cells. The current study showed that ENE may act as a potential drug candidate for treating osteoarthritis.

While physiological loads maintain cartilage health, both joint overload and abnormal joint mechanical loading contribute to osteoarthritis (OA) development. Here, we examined the role of abnormal mechanical loading on joint health by comparing the severity of OA development following a single overload event and repetitive joint overloads.

Cyclic tibial compression was applied to the left limbs of 26-week-old male mice at a peak load of 9N for either a single bout or daily bouts to initiate OA disease. Joint damage severity was morphologically examined using histology and microcomputed tomography at 6 weeks following the start of loading. Early-stage transcriptomic responses to loading were evaluated.

Joint damage was more severe at 6 weeks following a single bout of loading than after daily loading bouts. Severe cartilage damage, subchondral plate erosions, and soft tissue calcifications occurred following the single bout of loading. Daily loading bouts resulted in less severe cartilage damage and preserved subchondral plate integrity. A diverging transcriptomic response was identified in cartilage at 1 week with increased expression of fibrosis- and inflammation-related genes following a single bout of loading compared to daily loading.

Even applied at hyperphysiological load magnitudes known to initiate cartilage damage, repetitive loading may induce protective effects in the joint and attenuate OA progression over time relative to a single bout of loading. Our findings suggest the potential of mechanotherapies that use repetitive loading as disease-modifying treatments for OA disease.

Background/Objectives: Osteoarthritis (OA) is one of the most prevalent chronic conditions and significantly contributes to local and global disease burden. Common pharmaceuticals that are used to treat OA cause significant side effects, thus non-pharmaceutical bioactive alternatives have been developed that can impact OA symptoms without severe side-effects. One such alternative is the Red Algae Lithothamnion species (Litho). However, there is little mechanistic knowledge of its potential to effect OA gene expression, and a human in vitro model using commercially available cell lines to test its effectiveness has yet to be developed. Methods: Human osteoblast (hFOB 1.19. CRL-11372) and chondrocyte (C28/I2) cell lines were co-cultured indirectly using transwells. IL1-β was used to induce an inflammatory state and gene expression profiles following treatment were the primary outcome. Conclusions: Results indicated that the model was physiologically relevant, remained viable over at least seven days, untreated or following induction of an inflammatory state while maintaining hFOB 1.19. and C28/I2 cell phenotypic characteristics. Following treatment, Litho reduced the expression of inflammatory and pain associated genes, most notably IL-1β, IL-6, PTGS2 (COX-2) and C1qTNF2 (CTRP2). Confirmatory analysis with droplet digital PCR (ddPCR) revealed that Il-1β induced a significant reduction in C1qTNF2 at 7 days which was ameliorated with Litho treatment. These data present a novel and replicable co-culture model of inflammatory OA that can be used to investigate bioactive nutraceuticals. For the first time, this model demonstrated a reduction in C1qTNF2 expression that was mitigated by Red Algae Lithothamnion species.

Although mandibular autorotation concept (MAC) surgery is a novel technique for addressing long-term stability issues in patients with mandibular retrusion and open bite accompanied by temporomandibular joint osteoarthritis (TMJOA), studies on MAC surgery in animal models and its mechanisms are scarce. This study aimed to develop an animal model for anterior open bite and investigate the underlying histological and molecular mechanisms of TMJ changes, with the expectation of contributing to the MAC surgery concept.

Thirty-six, 5-weeks-old female Wistar rats were randomly divided into three groups: (1) Bite-raise group (2-mm resin added to the upper molars at 5 weeks of age) (2), Recovery group (resin added at 5 weeks of age and removed at 13 weeks of age), and (3) Control group (normal rats). Micro-CT imaging was used to assess 3D morphology and bone structure. Histological and immunohistochemical analyses were performed to evaluate the cartilage changes, bone cell differentiation, and extracellular matrix degradation. Gene expression of inflammatory factors (IL-1β, IL-6, TNF-α), TGF-β1, and Postn were measured by qPCR.

At 13 weeks of age, both Bite-raise and Recovery groups exhibited TMJOA-like changes, including decreased cartilage thickness and increased inflammatory gene expression. At 21 weeks of age, the Recovery group showed improved bone volume, reduced osteoclast activity, and lower MMP-13 and Postn levels than the Bite-raise group.

These results suggest the successful development of an animal model for anterior open bite and demonstrate that MAC surgery facilitates the recovery of compromised condyles.

Osteoarthritis is a degenerative joint disorder characterized by cartilage degradation, synovial inflammation, and altered subchondral bone structure. Recent insights have identified mitochondrial dysfunction as a pivotal factor in OA pathogenesis, contributing to chondrocyte apoptosis, oxidative stress, and extracellular matrix degradation. Disruptions in mitochondrial dynamics, including impaired biogenesis, mitophagy, and metabolic shifts from oxidative phosphorylation to glycolysis, exacerbate cartilage damage by promoting the production of reactive oxygen species and matrix-degrading enzymes such as ADAMTS and MMPs. This review explores the molecular mechanisms underlying mitochondrial dysfunction in OA, emphasizing its role in cartilage homeostasis and inflammation. Furthermore, it highlights emerging therapeutic strategies targeting mitochondrial pathways, including antioxidants, mitophagy enhancers, and metabolic modulators, as potential interventions to mitigate disease progression, which offer promising avenues for advancing personalized and disease-modifying treatments in OA.

Osteoarthritis (OA) is the most common degenerative arthropathy, impacting the quality of life for millions worldwide. It typically presents with chronic pain, stiffness, and reduced mobility in the affected joints. Nonsurgical treatments like physiotherapy or pharmacotherapy may provide limited relief and may have adverse effects and complications. Recently, low-dose radiation therapy (LDRT) has emerged as a potential alternative for managing OA, utilizing its anti-inflammatory effects. LDRT's anti-inflammatory effects involve modulating immune responses, reducing pro-inflammatory cytokines, and inducing apoptosis in inflammatory cells. Clinical studies show varying degrees of symptom relief, with some patients experiencing pain reduction and improved joint mobility while others show minimal response. The variability in LDRT treatment designs, radiation dosages, and patient populations complicates standardized treatment protocols and raises concerns about potential carcinogenic risks. Despite these issues, LDRT shows promise as an alternative to other OA treatments, especially for patients who don't respond to other treatments. This review aims to provide updated information on the effectiveness, mechanisms, and safety of LDRT in treating OA. We reviewed the literature of studies on the safety and efficacy of LDRT on affected joints by OA, its biological effects, potential therapeutic and adverse effects, application and contraindications, clinical outcomes, and clinical evidence in subjects with OA.

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

The outcome of major surgery is determined not only by the success of the procedure itself but also by its neurocognitive effects. We previously reported improved cognition following spine surgery (Müller et al. 2023 Spine ), but the mechanisms underlying these changes remain unknown.

We analyzed resting-state functional magnetic resonance images of 79 patients (mean/SD age: 71/7 years) acquired at baseline in this previously published trial. For 26 patients, data was additionally available at 3-months follow-up visits. To delineate large-scale connectivity, we calculated functional connectivity (FC) within and between three core neural networks, the central executive network (CEN), the salience network (SAL), and the default mode network (DMN).

FC between CEN and SAL predicted cognitive improvement (beta = 0.36, 95%-CI 0.28 to 0.45, P = 0.033). Average FC between all nodes of the CEN showed changes toward an increase after surgery (beta = 0.057, 95%-CI -0.01 to 0.123, P = 0.086). Further seed-based FC analyses revealed that this increase was most pronounced in the functional coupling between left dorsolateral prefrontal and right posterior parietal cortex (beta = 0.10, T(24) = 2.73, Punc  = 0.012, PFDR  = 0.035). The increase of CEN-FC correlated with individual enhancements of executive scores (beta = 0.34, 95%-CI 0.32 to 0.36, P = 0.034).

Integration of activity between the CEN and SAL networks predicted postoperative cognitive improvements, suggesting that less segregated large-scale functional networks may facilitate beneficial cognitive changes following surgery. Postoperative increases in functional coupling may serve as a biomarker for individual improvements in executive functions. These results indicate that surgery should not be routinely deferred in elderly patients due to concerns about postoperative neurocognitive complications. Moreover, our findings highlight potential targets for non-invasive brain stimulation interventions aimed at preventing neurocognitive complications.

The caterpillar of Premolis semirufa, known as Pararama, is found in the Brazilian Amazon, primarily on rubber trees of the genus Hevea. Pararamosis is an inflammatory disease resulting from accidental contact with the caterpillar's bristles, leading to acute and chronic symptoms. Chronic exposure can cause significant osteoarticular deformities, similar to those seen in osteoarthritis and rheumatoid arthritis, due to cartilage degradation and synovial inflammation. Currently, there are no specific treatments for Pararamosis, and research on the molecular mechanisms of the caterpillar's venom and its role in disease pathogenesis is limited. The chronic changes in Pararamosis are thought to be linked to chondrocyte activation and the NF-κB signaling pathway, influenced by the toxic components in the bristles. Understanding these interactions is crucial for developing preventive measures and therapeutic strategies, especially for rubber tappers at risk in the Amazon region.

This study investigated the effects of P. semirufa bristle extracts on human chondrocytes, focusing on the activation mechanism of the NF-κB transcription factor and the expression of osteoarthritis markers. Cell viability tests indicated that the extracts did not significantly affect chondrocyte survival. However, supernatant analysis revealed a time- and dose-dependent increase in IL-6 and IL-8 levels. Additionally, the expression of NF-κB and its inhibitor, IκB, was assessed, showing higher levels of phosphorylated IκB, which induces its proteosomal degradation, compared to the negative control, while native IκB expression was greater in the control group. Furthermore, the gene expression profile of treated chondrocytes demonstrated modulation in matrix metalloproteinases (MMPs), aggrecan (ACAN), collagen type II (COL2A1), interleukins (IL6 and IL8), and complement system molecules.

These findings highlight the significant impact of P. semirufa bristle extracts on human chondrocyte activation and the inflammatory processes associated with pararamosis.

Orthopedics is one field that greatly benefits from the new ideas provided by regenerative medicine. This review pulls together the most recent publications involving stem cell therapy, platelet-rich plasma, growth factor, gene therapy, tissue engineering, stem cell-derived extracellular vesicles, and other regenerative technologies in the context of bone, cartilage, tendon, and ligament healing. Recent studies show that these new therapies can alter cell development, division, and production of fiber and ground substance to remodel tissues. Nevertheless, the clinical application has several issues such as the standardization of cell procurement and preparation, the control of cytokine/gene delivery, the revascularization of tissues, and the requirements of large samples, positively controlled clinical trials. More research must be conducted to overcome such barriers and make practicing more applicable in real life.

Osteoarthritis (OA) is one of the most common degenerative diseases, and the number of patients has been constantly increasing. Non-steroidal anti-inflammatory drugs, glucocorticosteroids, opioids, etc., and surgical procedures, e.g. arthroplasty, are among the most common methods of treatment. There are reasons to believe that the gut microbiome (GMB) may influence inflammatory processes occurring in the pathomechanism of OA. The inflammatory processes occurring in the intestines may lead to disruption of tight junctions and increased concentrations of pro-inflammatory cytokines, resulting in increased permeability of intestines, causing low-grade inflammation, including in the joints. Methods of altering the GMB composition to reduce the inflammatory and joint degenerative processes are known only to some extent, and long-term research is required. Osteoarthritis, a particularly well-known and very widespread disease due to the aging population, is characterized by moderate and local inflammation. It occurs due to the effects of biomechanical cartilage wear with damage of joint structures, primarily through degenerative processes. OA represents a therapeutic challenge, and any element that can influence its inhibition is highly sought after. Therefore, these methods seem to offer a promising additional approach to treatment.

This narrative review intends to provide thorough information on the anti-inflammatory activities of Alpinia plants, the largest genus of the family Zingiberaceae. The articles were searched on the PubMed database using 'Alpinia AND anti-inflammatory activity' as the keywords, filtered to articles published from 2020 to 2024 and free full-text. Of the approximately 248 members of the genus Alpinia plants, the most commonly studied for their anti-inflammatory activities are A. galanga, A. officinarum, A. zerumbet, and A. oxyphylla. Only A. galanga, A. officinarum, and A. zerumbet have been studied in humans. Studies in animal models revealed that the plants contributed as exogenous antioxidants, reduced proinflammatory cytokines, inhibited proinflammatory enzymes, improved gastric acid and gastrointestinal motility, and promoted ulcer healing. The terpenoids, flavonoids (such as kaempferol, quercetin, and galangin), and diarylheptanoids obtained from the rhizomes of these plants may crucially play important roles in their anti-inflammatory activities. These plants did not show toxicity toward numerous normal cell lines (RAW 264.7, IEC-6, HepG2, MT-4, NIH-3T3, Vero cells, human peripheral blood mononuclear cells, and HaCaT) but were toxic to cancer cell lines (HT29). In humans, A. galanga was studied for its effects as psychostimulants improving mental health, improving sperm motility, and erectile dysfunction. Similarly, A. officinarum could improve sperm morphology and idiopathic infertility, whereas A. zerumbet worked as a cardio-myorelaxant in patients with cardiovascular diseases.

Articular cartilage damage presents a significant clinical challenge, with limited options for effective regeneration. Mesenchymal stromal cells (MSCs) derived from Wharton's jelly (WJ) are a promising cell source for cartilage repair due to their regenerative and immunomodulatory properties. While undifferentiated MSCs have demonstrated potent immunoregulatory effects, the immunomodulatory potential of chondrocytes derived from WJ-MSCs remains underexplored, particularly under inflammatory conditions. This study investigates the differential cytokine expression profiles of WJ-MSC-derived chondrocytes and undifferentiated MSCs under inflammatory stimulation with phytohemagglutinin (PHA) to understand their immunomodulatory capacities.

WJ-MSCs were differentiated into chondrocytes using a micromass culture system. Differentiated chondrocytes were then co-cultured with immune cells under PHA-induced inflammatory conditions. Control groups included co-cultured cells without PHA activation and chondrocytes activated with PHA in the absence of immune cell interaction. Cytokine expression profiles were analyzed using the RT2 Customized Gene Array to evaluate pro- and anti-inflammatory markers. Morphological changes were assessed microscopically. The immunomodulatory responses of chondrocytes were compared to those of undifferentiated MSCs under the same experimental conditions.

Chondrocytes co-cultured with immune cells under PHA activation exhibited downregulation of IDO, HLA-G, PDGF, IL-10, TNF-α, IL-6, and IFN-γ compared to undifferentiated MSCs in similar conditions. In non-PHA co-cultured conditions, chondrocytes showed increased expression of IL-6, IFN-γ, IL-4, VEGF, iNOS, PDGF, PTGS-2 and TGF-β, while TNF-α, IL-10, IDO and HLA-G were decreased. In contrast, chondrocytes activated with PHA without immune cell interaction displayed reduced expression of HLA-G and TNF-α, with no significant changes in IL-6, IFN-γ, IL-4, IL-10, VEGF, PDGF, PTGS-2, TGF-β, IDO, and iNOS compared to PHA-stimulated undifferentiated MSCs.

This study demonstrates that chondrocytes derived from WJ-MSCs exhibit limited immunomodulatory potential compared to undifferentiated MSCs, particularly under PHA-induced inflammatory conditions. Undifferentiated MSCs showed superior regulation of key cytokines associated with immune modulation. These findings suggest that maintaining MSCs in an undifferentiated state may be advantageous for therapeutic applications targeting inflammatory conditions, such as osteoarthritis. Future research should explore strategies to enhance the immunomodulatory efficacy of chondrocytes, potentially through genetic modification or adjunctive therapies.

The sustainable utilization of biomass-derived bioactives addresses the growing demand for natural health products and supports sustainable development goals by reducing reliance on synthetic chemicals in healthcare. Cannabis sativa biomass, in particular, has emerged as a valuable resource within this context. This study focuses on the hydroethanolic extract of C. sativa leaves (CSE), which exhibited significant levels of phenolic compounds contributing to robust antioxidant activity. Evaluation using potassium ferricyanide, ABTS, and DPPH methods revealed potent radical scavenging activity comparable to the Trolox standard. UPLC-MS/MS profiling identified cannabinoids as the predominant secondary metabolites in CSE, with flavonoids also present in substantial quantities. This study investigated the anti-inflammatory potential of CSE on RAW 264.7 macrophages and IL-1β-stimulated C-20/A4 immortalized human chondrocytes, demonstrating protective effects without cytotoxic or mutagenic effects. Mechanistically, CSE reduced inflammation by inhibiting the MAPK and NF-κB signaling pathways. In silico approaches showed the ability of CSE's main metabolites to bind and influence MAPK and NF-κB activity, confirming in vitro evidence. Incorporating C. sativa leaf extract into a hyaluronic acid-based formulation showed biotechnological promise for treating joint inflammation. Future research should aim to elucidate the molecular mechanisms underlying these effects and explore the potential of CSE-derived compounds in mitigating osteoarthritis progression. This approach highlights the significance of utilizing annually increasing biomass waste for sustainable bioactivity and environmental impact reduction.

This study aimed to compare the use of cortisone (C), intra-articular injected at the end of hip arthroscopy in patients with femoroacetabular impingement (FAI), to a new Class III medical device based on hydrolyzed collagen peptides 'PEPTYS' (P) and, to investigate potential associations among preoperative symptoms and hip function, outcomes after arthroscopic surgery and presence of inflammatory biomarkers in synovial fluids (SFs) at basal condition.

The two treatments were administrated to patients scheduled for arthroscopy with simple blind randomization sampling. Based on the sample size calculation, the number necessary to recruit was at least 20 patients for the C group and 20 for the P group. SFs, when available, were obtained by aspiration just prior to surgical intervention. At the baseline, osteoarthritis (OA) severity was assessed with a radiographic scoring system (Tönnis classification). Physical examination and clinical assessment using the Hip disability and Osteoarthritis Outcome Score (HOOS) and visual analogue scale (VAS) score for pain were performed at the time of surgery and at 1 and 6 months of follow-up. At the time of surgery, chondral (Outerbridge score) and labral pathology based on direct arthroscopic visualization were also evaluated.

Forty-seven FAI patients were enroled, with a median age of 35 years with a standard deviation (SD) of 10.6 and a body mass index of 24.3kg/m² with an SD of 4.5. 24 patients were treated with C and 23 with P. Both treatments did not show any statistically significant difference in hip function and pain. High expression of inflammatory molecules in SFs was correlated with the worst post-operative articular function.

Our study showed that the use of P was completely comparable to cortisone. Therefore, PEPTYS might be a valuable candidate to improve early recovery, in terms of pain and function, from arthroscopic FAI treatment.

Level III, comparative and randomized study.

Osteoarthritis is a progressive, irreversible debilitating whole joint disease that affects millions of people worldwide. Despite the availability of various options (non-pharmacological and pharmacological treatments and therapy, orthobiologics, and surgical interventions), none of them can definitively cure osteoarthritis in patients. Strategies based on the controlled release of therapeutic compounds via biocompatible materials may provide powerful tools to enhance the spatiotemporal delivery, expression, and activities of the candidate agents as a means to durably manage the pathological progression of osteoarthritis in the affected joints upon convenient intra-articular (injectable) delivery while reducing their clearance, dissemination, or side effects. The goal of this review is to describe the current knowledge and advancements of controlled release to treat osteoarthritis, from basic principles to applications in vivo using therapeutic recombinant molecules and drugs and more innovatively gene sequences, providing a degree of confidence to manage the disease in patients in a close future.

Osteoarthritis (OA) is a degenerative whole-joint disease in which the synovium and joint cartilage become inflamed and damaged. The essential role of inflammation in the development of OA has been recognized recently. Accordingly, simultaneous regulation of local inflammation and tissue degeneration is proposed as a promising therapeutic strategy. Herein, multifunctional biomimetic apoptotic nanovesicles (Apo-NVs) are constructed with plasma membrane derived from apoptotic T cells. The anti-inflammatory microRNA-124 is further encapsulated into Apo-NVs in the hope of achieving an enhanced immunomodulatory effect. It is found that apoptotic nanovesicles, including Apo-NVs and Apo-NVs-miR-124, both efficiently promote the M2 repolarization of M1 macrophages and inhibit the degenerative phenotype of chondrocytes. Further in vivo studies show that Apo-NVs and Apo-NVs-miR-124 alleviate synovial inflammation and protect cartilage tissue from degeneration in OA mice. The study highlights the potential of Apo-NVs in treating OA and other inflammation-related diseases.

Inflammation and extracellular matrix (ECM) degradation are two major factors involved in the pathogenesis of osteoarthritis (OA). Wedelolactone, a natural compound classified as a coumestan, is isolated from the medicinal plants Eclipta alba and Wedelia calendulacea. In this study, we assessed the protective effects of Wedelolactone on chondrocytes in OA. Our findings show that pretreatment with Wedelolactone effectively inhibited the IL-1β-induced upregulation of COX‑2, iNOS, TNF-α, and IL6 in chondrocytes, contributing to inflammation suppression. Moreover, pretreatment with Wedelolactone followed by IL-1β treatment significantly increased the expression of Collagen II and SOX9, while decreasing the expression of Adamts5, MMP1, MMP3, and MMP13, thereby promoting ECM protection. Through Network pharmacology Analysis, we identified 14 key targets that link Wedelolactone and OA. GO and KEGG pathway analysis suggested that Wedelolactone primarily impacted OA by targeting inflammatory responses, particularly the NF-κB signaling pathway. Further studies demonstrated Wedelolactone prevented IL-1β-induced activation of NF-κB signaling pathway by inhibiting the translocation of p65 and the preventing the degradation of IκBα in human chondrocytes. Molecular docking studies also indicated that Wedelolactone can directly bind to the NF-κB complex, thereby inhibited the nuclear localization of p65. In vivo experiments demonstrated that Wedelolactone can alleviate cartilage damage in DMM mice model. In summary, Wedelolactone appears to mitigate inflammation and cartilage degeneration by suppressing the NF-κB signaling pathway, thereby alleviating OA progression. Our results suggested Wedelolactone may offer therapeutic advantages for OA treatment.

Transient receptor potential channel 1 (TRPC1) is a widely expressed mechanosensitive ion channel located within the endoplasmic reticulum membrane, crucial for refilling depleted internal calcium stores during activation of calcium-dependent signaling pathways. Here, we have demonstrated that TRPC1 activity is protective within cartilage homeostasis in the prevention of cellular senescence-associated cartilage breakdown during mechanical and inflammatory challenge. We revealed that TRPC1 loss is associated with early stages of osteoarthritis (OA) and plays a nonredundant role in calcium signaling in chondrocytes. Trpc1-/- mice subjected to destabilization of the medial meniscus-induced OA developed a more severe OA phenotype than WT controls. During early OA development, Trpc1-/- mice displayed an increased chondrocyte survival rate; however, remaining cells displayed features of senescence including p16INK4a expression and decreased Sox9. RNA-Seq identified differentially expressed genes related to cell number, apoptosis, and extracellular matrix organization. Trpc1-/- chondrocytes exhibited accelerated dedifferentiation, while demonstrating an increased susceptibility to cellular senescence. Targeting the mechanism of TRPC1 activation may be a promising therapeutic strategy in OA prevention.

The gut microbiome, a complex ecosystem of microorganisms in the digestive tract, has emerged as a critical factor in human health, influencing metabolic, immune, and neurological functions. This review explores the connection between the gut microbiome and orthopedic health, examining how gut microbes impact bone density, joint integrity, and skeletal health. It highlights mechanisms linking gut dysbiosis to inflammation in conditions such as rheumatoid arthritis and osteoarthritis, suggesting microbiome modulation as a potential therapeutic strategy. Key findings include the microbiome's role in bone metabolism through hormone regulation and production of short-chain fatty acids, crucial for mineral absorption. The review also considers the effects of diet, probiotics, and fecal microbiota transplantation on gut microbiome composition and their implications for orthopedic health. While promising, challenges in translating microbiome research into clinical practice persist, necessitating further exploration and ethical consideration of microbiome-based therapies. This interdisciplinary research aims to link digestive health with musculoskeletal integrity, offering new insights into the prevention and management of bone and joint diseases.

The object of this study was to propose a Wnt5a-matrix metalloproteinase (MMP)-13 dependent signaling axis for osteoarthritis (OA) progression. To this end, the chondrocytes were isolated from both OA patients and normal controls. The chondrocytes were treated with diverse concentrations of Wnt5a (0, 50, 100, and 200 ng/mL), respectively. The expression levels of Wnt5a, MMP-13, and Collagen type II were examined using reverse transcription-polymerase chain reaction and western blotting. At the same time, the cell proliferation and cell apoptosis of chondrocytes were also observed. Compared with control tissues, the activities of Wnt5a and MMP-13 were significantly enhanced in chondrocytes of OA patients. Treated with different concentrations of Wnt5a (0, 50, 100, and 200 ng/mL), chondrocyte cell proliferation was clearly downregulated. At the same time, the chondrocyte cell apoptosis was obviously accelerated. The expression pattern of Collagen type II was same as cell proliferation manner. Co-treatment of MMP-13 siRNA could significantly compensate the functions of Wnt-5a administration, suggesting MMP-13 was a direct target of Wnt-5a. Collectively, the study speculated a novel Wnt5a-MMP-13 molecular mechanism for OA progression and shed an innovative signaling axis for the disorder.

This study aimed to assess the effectiveness of joint lavage in managing knee osteoarthritis (OA) by evaluating its effect on pain relief, inflammatory markers, cartilage-degrading enzymes, and oxidative stress.

Seventy patients with Kellgren-Lawrence grade 2 or 3 knee OA were selected for this single-center study. Joint lavage was performed, and pain and function were measured using the visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores at baseline and 24 weeks postintervention. Synovial fluid samples were collected at baseline, before lavage, and 24 weeks postintervention. Samples were stored at -80°C and analyzed in batches to minimize variability. At the time of analysis, the samples were thawed and evaluated for levels of proinflammatory cytokines, interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), matrix metalloproteinase-3 (MMP-3), and total oxidant status (TOS), and oxidative stress index (OSI).

Postintervention, VAS, and WOMAC scores significantly decreased (P < 0.001), with 100% achieving the minimal clinically important difference (MCID). Patient acceptable symptom state (PASS) rates varied: VAS (80%), WOMAC pain (50%), function (81.4%), and total (84.3%). Cytokine levels (IL-1β, IL-6, TNF-α) and MMP-3 significantly decreased (P < 0.001), along with TOS and OSI. Baseline TNF-α, IL-6, and IL-1β levels were significantly correlated with improvements in VAS and WOMAC scores. Moderate correlations were observed between reductions in IL-6/TNF-α and improvements in VAS/WOMAC. No significant associations were found between confounders and outcomes.

Joint lavage resulted in marked pain relief and functional improvement while significantly reducing inflammatory markers, cartilage-degrading enzymes, and oxidative stress.

Osteoarthritis (OA) remains a challenging joint disorder necessitating effective anti-inflammatory interventions. In this study, our primary objective was to establish an in vitro protocol that replicates the clinical investigation of anti-inflammatory drugs intended for OA management. Focusing on recombinant IL-10 (r.IL-10) as a potential anti-inflammatory treatment, we designed and implemented two distinct protocols to evaluate the efficacy of r.IL-10 in modulating chondrocyte and synoviocyte inflammation.The experimental design involved sequential stimulation with IL-1β and TNF-α for 24 h, followed by washing (model 1) or not washing (model 2) the cells before r.IL-10 treatment. Samples were collected after 6-24 h of treatment. Cellular responses were evaluated by quantifying gene expression and synthesis of key inflammatory cytokines and proteases.The expression and synthesis of inflammatory cytokines and proteases was significantly affected by washing and treatment time. The expression of IL-1β, TNF-α, IL-8, MMP-13, and ADAMTS5 were effectively reduced in r.IL-10-treated chondrocytes and synoviocytes in model 2 after 24 h, particularly at concentrations of 10 and 20 ng/mL. r.IL-10 treatment significantly increased IL-6 gene expression in chondrocytes at all time points. However, in synoviocytes, IL-6 expression was significantly lower in model 2 after 24 h of r.IL-10 treatment. r.IL-10 treatment significantly decreased IL-1β and TNF-α content in synoviocyte supernatants, particularly in model 2 at concentrations of 10 and 20 ng/mL after 6 and 24 h. r.IL-10 treatment in chondrocytes led to a significant decrease in IL-1β supernatant concentrations in model 2 after 24 h only.This study demonstrated that r.IL-10 treatment effectively reduces key inflammatory markers and matrix metalloproteinase activity in both chondrocytes and synoviocytes, particularly in model 2 where cells were not washed prior to treatment. These findings highlight r.IL-10's potential as a robust anti-inflammatory agent for OA management and suggest its critical role in developing effective therapeutic strategies for OA.

Osteoarthritis (OA), a joint disease associated with inflammatory processes, contributes to joint destruction. Esculin (ESC) extracted from the stem bark of Fraxinus rhynchophylla Hance has been shown to possess anti-inflammatory properties. In this study, we investigated the effect of ESC on chondrocytes treated with IL-1β and its molecular mechanism. The importance and potential mechanism of ESC in the progression of OA were evaluated. The viability of chondrocytes after exposure to ESC was examined through the CCK-8 assays. The cells were then subjected to quantitative polymerase chain reaction (qPCR), western blot, and enzyme-linked immunosorbent assay (ELISA) techniques to analyze the degradation of the extracellular matrix (ECM) and occurrence of inflammation. The NF-κB mechanism was evaluated by western blot analysis, immunofluorescence (IF), and luciferase reporter assay. Molecular docking was performed to allow for predictions on proteins that interact with ESC. Moreover, the significance of Sirt1 was explored through a knockdown experiment based on siRNA. Micro-computed tomography (CT), H&E, Safranin O-Fast Green (S-O), and immunohistochemical analyses were carried out to assess the treatment efficacy of ESC on OA in destabilization of medial meniscus (DMM) models. ESC treatment effectively inhibited ECM degradation, modulated the levels of pro-inflammatory factors, and regulated the NF-κB signaling in chondrocytes exposed to IL-1β. Mechanistically, we found that ESCs bound to Sirt1 to inhibit the activity of the NF-κB mechanism. Furthermore, ESC treatment suppressed OA progression in the DMM models. Our findings reveal that ESC ameliorates OA progression via modulating the Sirt1/NF-κB axis. This demonstrates that ESC has the potential to be applied in the treatment of OA.

To further our understanding of the role of tumor necrosis factor (TNF)α on the inflammatory response in chondrocytes.

We explored the effects of TNFα on the transcriptome of epiphyseal chondrocytes from newborn C57BL/6 mice at the total and single cell (sc) resolution.

Gene set enrichment analysis of total RNA-Seq from TNFα-treated chondrocytes revealed enhanced response to biotic stimulus, defense and immune response and cytokine signaling and suppressed cartilage and skeletal morphogenesis and development. scRNA-Seq analyzed 14,239 ​cells and 24,320 genes and distinguished 16 ​cell clusters. The more prevalent ones were constituted by limb bud and chondrogenic cells and fibroblasts comprising ∼73 ​% of the cell population. Genes expressed by joint fibroblasts were detected in 5 clusters comprising ∼45 ​% of the cells isolated. Pseudotime trajectory finding revealed an association between fibroblast and chondrogenic clusters which was not modified by TNFα. TNFα decreased the total cells recovered by 18.5 ​% and the chondrogenic, limb bud and mesenchymal clusters by 32 ​%, 27 ​% and 7 ​%, respectively. TNFα had profound effects on the insulin-like growth factor (IGF) axis decreasing Igf1, Igf2 and Igfbp4 and inducing Igfbp3 and Igfbp5, explaining an inhibition of collagen biosynthesis, cartilage and skeletal morphogenesis. Ingenuity Pathway Analysis of scRNA-Seq data revealed that TNFα enhanced the osteoarthritis, rheumatoid arthritis, pathogen induced cytokine storm and interleukin 6 signaling pathways and suppressed fibroblast growth factor signaling.

Epiphyseal chondrocytes are constituted by diverse cell populations distinctly regulated by TNFα to promote inflammation and suppression of matrix biosynthesis and growth.

The potential effects of insulin therapy on osteoarthritis (OA) risk are poorly understood. This study aimed to explore the causal relationship between insulin therapy and OA.

Mendelian randomization (MR) analysis was performed to examine the association between genetically proxied inhibition of insulin targets and the risk of overall, hip (HOA) and knee OA (KOA). We then performed univariable MR using summary statistics regarding insulin target genes derived from the DrugBank database. Data related to blood glucose reduction levels were used as a proxy for insulin levels. Two phenotypes, type 2 diabetes, and glycosylated hemoglobin levels, were selected as positive controls to confirm the direction and validity of the proxies. The OA datasets were derived from the UK Biobank cohort. Multivariable MR was adjusted for body mass index, sedentary behavior, cigarette smoking, frequency of alcohol intake, age, and genetic sex.

Genetically proxied insulin therapy was associated with an increased risk of overall OA [odds ratio (OR):1.2595; 95% confidence interval (CI):1.0810-1.4675] and HOA (OR:1.4218; 95%CI:1.1240-1.7985), which remained consistent across multiple MR methods. After adjusting for confounders, we found evidence supporting a significant causal link with a higher risk of overall OA and HOA. A further two-step MR analysis revealed no significant mediation effects from the six mediators in the associations.

There was a causal association between genetically proxied insulin therapy and a higher risk of OA, especially HOA.

Arthropathy is a common complication in haemophilia and decreases quality of life. It has been known that concentrations of β-hydroxybutyrate (BHB) in blood are increased by a ketogenic diet, and elevated levels of circulating BHB restricts the progression of inflammation-mediated joint pathological changes. We hypothesized that elevation of blood BHB concentrations could be effective for reducing the progression of bleeding-induced arthropathy by moderating the inflammatory responses of macrophages. In this study, we investigated whether BHB alleviates the arthropathy caused by repeated intra-articular blood injection in rats. To increase blood BHB levels, rats were fed with ketogenic diet. Repeated intra-articular blood injection induced significant joint swelling, whereas ketogenic diet intake significantly increased blood BHB concentrations and ameliorated the joint swelling. The periarticular tissue-fibrosis observed in the control diet intake group appeared to be significantly alleviated in the ketogenic diet intake group. In addition, the IL-1β, which is involved in the progression of arthropathy, levels in the supernatants of blood-exposed macrophages derived from THP-1 cell line were significantly suppressed by BHB supplementation. In summary, BHB moderated the pathological joint changes caused by intra-articular blood exposure.

Osteoarthritis (OA) is a common degenerative joint disease that poses a significant global healthcare challenge due to its complexity and limited treatment options. Advances in metabolomics have provided insights into OA by identifying dysregulated metabolites and their connection to altered signaling pathways. However, a comprehensive understanding of these biomarkers in OA is still required.

This systematic review aims to identify metabolomics biomarkers associated with dysregulated signaling pathways in OA, using data from various biological samples, including in vitro models, animal studies, and human research.

A systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Data were gathered from literature published between August 2017 and May 2024, using databases such as "PubMed," "Scopus," "Web of Science," and "Google Scholar." Studies were selected based on keywords like "metabolomics," "osteoarthritis," "amino acids," "molecular markers," "biomarkers," "diagnostic markers," "inflammatory cytokines," "molecular signaling," and "signal transduction." The review focused on identifying key metabolites and their roles in OA-related pathways. Limitations include the potential exclusion of studies due to keyword selection and strict inclusion criteria.

The meta-analysis identified dysregulated metabolites and associated pathways, highlighting a distinct set of related metabolites consistently altered across the studies analyzed. The dysregulated metabolites, including amino acids, lipids, and carbohydrates, were found to play critical roles in inflammation, oxidative stress, and energy metabolism in OA. Metabolites such as alanine, lysine, and proline were frequently linked to pathways involved in inflammation, cartilage degradation, and apoptosis. Key pathways, including nuclear factor kappa B, mitogen-activated protein kinase, Wnt/β-catenin, and mammalian target of rapamycin, were associated with changes in metabolite levels, particularly in proinflammatory lipids and energy-related compounds.

This review reveals a complex interplay between dysregulated metabolites and signaling pathways in OA, offering potential biomarkers and therapeutic targets. Further research is needed to explore the molecular mechanisms driving these changes and their implications for OA treatment.

Osteoarthritis (OA) is a chronic progressive degenerative joint disease that affects a significant portion of the equine population and humans worldwide. Current treatment options for equine OA are limited and incompletely curative. Horses provide an excellent large-animal model for studying human OA. Recent advances in the field of regenerative medicine have led to the exploration of extracellular vesicles (EVs)-cargoes of microRNA, proteins, lipids, and nucleic acids-to evaluate their diagnostic value in terms of disease progression and severity, as well as a potential cell-free therapeutic approach for equine OA. EVs transmit molecular signals that influence various biological processes, including the inflammatory response, apoptosis, proliferation, and cell communication. In the present review, we summarize recent advances in the isolation and identification of EVs, the use of their biologically active components as biomarkers, and the distribution of the gap junction protein connexin 43. Moreover, we highlight the role of mesenchymal stem cell-derived EVs as a potential therapeutic tool for equine musculoskeletal disorders. This review aims to provide a comprehensive overview of the current understanding of the pathogenesis, diagnosis, and treatment strategies for OA. In particular, the roles of EVs as biomarkers in synovial fluid, chondrocytes, and plasma for the early detection of equine OA are discussed.