Degenerative Joint Disorder Research Articles

Sirt1 overexpression inhibits chondrocyte ferroptosis via Ftl deacetylation to suppress the development of osteoarthritis.

Osteoarthritis (OA) is a chronic degenerative joint disorder characterized by an imbalance in chondrocyte metabolism. Ferroptosis has been implicated in the pathogenesis of OA. The role of Sirt1, a deacetylase, in mediating deacetylation during ferroptosis in OA chondrocytes remains underexplored. This study aimed to elucidate the mechanisms by which Sirt1 influences chondrocyte ferroptosis in the development of OA. In vitro and in vivo models of OA were established using IL-1β-induced mouse chondrocytes and a destabilization of the medial meniscus (DMM) mouse model, respectively. Ferroptosis was evaluated through measurements of cell viability, lactate dehydrogenase (LDH) release, intracellular levels of Fe2+, glutathione (GSH), malondialdehyde (MDA), lipid reactive oxygen species (ROS), propidium iodide staining, and Western blot analysis. The underlying mechanisms were further investigated using quantitative real-time polymerase chain reaction, Western blotting, immunoprecipitation (IP), co-immunoprecipitation (Co-IP), and glutathione-S-transferase pulldown assays. In vivo validation was performed via Safranin O staining. IL-1β induced ferroptosis and increased histone acetylation, effects that were partially reversed by Sirt1 overexpression. Mechanistically, Sirt1 overexpression upregulated ferritin light polypeptide (Ftl) expression by deacetylating Ftl at the K181 residue. Ftl knockdown inhibited the ferroptosis-enhancing effect of Sirt1 overexpression in chondrocytes. In vivo studies showed that Sirt1 overexpression mitigated the progression of OA and reduced ferroptosis in the DMM-induced OA mouse model. Our findings confirm that Sirt1 overexpression promotes Ftl expression through deacetylation at the K181 site, thereby suppressing chondrocyte ferroptosis and attenuating the progression of OA. These results suggest a potential therapeutic target for OA treatment.

Formulation and Characterization of Glucosamine Sulphate Potassium Chloride (GSPC) Loaded Emulgel for the Treatment of Osteoarthritis.

Osteoarthritis (OA) is becoming a major medical burden worldwide due to changing lifestyles and aging populations. Osteoarthritis is a disease characterized by a variety of anatomic and physiological changes to joints, including cartilage degradation, bone remodeling, and the formation of osteophytes. These changes cause pain, stiffness, swelling, and limitations in joint function. Glucosamine serves as a fundamental constituent for cartilage, the resilient connective tissue responsible for cushioning joints. Glucosamine Sulphate Potassium Chloride (GSPC) supplementation is widely employed to mitigate symptoms linked to osteoarthritis, a degenerative joint disorder hallmarked by cartilage degradation. Palliative care aims at minimizing pain and disability and improving function, performance, and quality of life. In this study, the emulgel formulation of GSPC was developed and checked for its potential. Currently, OA does not have a definitive treatment. Since conventional dosage forms cannot deliver the active drug content at a predefined target site in a predictable manner throughout the treatment period, a new carrier system is always required. Considering their reduced size, targeting potential, and site specificity, nanocarrier-based approaches could hold an answer to shortcomings associated with conventional routes. Thus, the objective of the current study was to formulate and characterize glucosamine sulphate potassium chloride-loaded emulgel for the treatment of osteoarthritis. Microemulsion of glucosamine sulphate potassium chloride was formulated using a spontaneous emulsification method comprising of oleic acid (oil phase), Tween 80, Tween 20 (surfactant) and PEG 400, Span 80 (co-surfactant), and distilled water (aqueous phase). The microemulsions were evaluated for surface morphology, globule size, poly-dispersibility index (PDI), zeta potential, and viscosity, and the final batch of microemulsions was selected. The optimized microemulsion contained 35% co-surfactant (propylene glycol), 20% surfactant (Tween 20), and 15% oil (oleic acid) and glucosamine sulphate potassium chloride in a dose of 60 mg, which has sufficient drug loading capacity with a droplet size of 182 nm for optimized formulation. The optimized microemulsion formulation was added to gel prepared by Carbopol 934 in a 1:1 (w/w) ratio, leading to the formulation of glucosamine sulphate potassium chloride- containing emulgel. The prepared emulgel was further evaluated for viscosity, drug content, pH, and in-vitro drug release. Emulgel formulation (F6) showed 88% drug release after 6 hours, and it followed the Higuchi model. Glucosamine Sulphate Potassium Chloride (GSPC) is used in the treatment of OA by increasing the production of proteoglycans, which can cause the cartilage to break down. Emulgel formulation (F3) showed 75.41% drug release, and formulation (F6) showed 88% drug release after 6 h. Therefore, it may be concluded that an emulgel of GSPC can be used as a controlled-release dosage form of the drug for local application in OA.

Innovative Biotherapies and Nanotechnology in Osteoarthritis: Advancements in Inflammation Control and Cartilage Regeneration.

Osteoarthritis (OA) is among the most prevalent degenerative joint disorders worldwide, particularly affecting the aging population and imposing significant disability and economic burdens. The disease is characterized by progressive degradation of articular cartilage and chronic inflammation, with no effective long-term treatments currently available to address the underlying causes of its progression. Conventional therapies primarily manage symptoms such as pain and inflammation but fail to repair damaged tissues. Emerging biotherapies and regenerative medicine approaches offer promising alternatives by addressing cartilage repair and inflammation control at the molecular level. This review explores the recent advancements in biotherapeutic strategies, including mesenchymal stem cell (MSC) therapy, growth factors, and tissue engineering, which hold the potential for promoting cartilage regeneration and modulating the inflammatory microenvironment. Additionally, the integration of nanotechnology has opened new avenues for targeted drug delivery systems and the development of innovative nanomaterials that can further enhance the efficacy of biotherapies by precisely targeting inflammation and cartilage damage. This article concludes by discussing the current clinical applications, the ongoing clinical trials, and the future research directions necessary to confirm the safety and efficacy of these advanced therapies for OA management. With these advancements, biotherapies combined with nanotechnology may revolutionize the future of OA treatment by offering precise and effective solutions for long-term disease management and improved patient outcomes.

Axis I diagnosis profile according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD): comparison between hospital-based orofacial pain clinic and dental academic-based orofacial pain clinic.

Temporomandibular disorder (TMD) is considered a complex disorder that follows the biopsychosocial model. The current study aimed to explore the effect of clinic location and referring physicians on the distribution of Axis I diagnoses according to the Diagnostic Criteria for TMD (DC/TMD). Eighty-eight patients from a dental school Orofacial Pain Clinic (DentalOFP) and 104 patients from a hospital Orofacial Pain Clinic (HospitalOFP) were examined by the same dentist who was certified as a DC/TMD examiner and compared. Significant differences between the two clinics were noted, including age (p = 0.002), gender (p = 0.019), symptom duration (p < 0.001), and referring physician's profile (p < 0.001). While 55.7% of referring physicians were dentists in the DentalOFP clinic, only 13.5% of referring physicians were dentists in the HospitalOFP clinic. DentalOFP clinic presented with characteristics of a tertiary clinic, as to female: male ratio and longer symptom duration. Significant differences were found as to intra-articular disorders (IAD) (p = 0.019), degenerative joint disorder (DJD) (p = 0.041), and subluxation (p = 0.015). There were no significant differences as to local myalgia (p = 0.128), myofascial pain with referral (p = 0.389), and arthralgia (p = 0.096). Multiple parameters, such as age, gender, symptom duration, primary vs. tertiary clinic, clinic location, and referring physicians may affect the overall DC/TMD Axis I profile. This study supports abandoning the term TMD. It is suggested to assess each Axis I diagnosis separately, and for each Axis I diagnosis, to follow the International Classification of Orofacial Pain (ICOP), as to primary vs. secondary etiologies, and acute vs. chronic conditions, to provide appropriate treatment.

The Annexin A1 Protein Mimetic Peptide Ac2-26 prevents cellular senescence of CHON-001 chondrocytes against tumor necrosis factor-α via the Nrf2/NF-κB pathway.

Osteoarthritis (OA) is a degenerative joint disorder characterized by progressive cartilage degradation. Excessive oxidative stress (OS), inflammatory responses, extracellular matrix breakdown, and cellular senescence of chondrocytes play crucial roles in the pathological development of OA. Currently, curing OA remains a significant challenge. In this study, we aimed to elucidate the protective effects of Annexin A1 protein Mimetic Peptide (Ac2-26) against tumor necrosis factor-α (TNF-α)-induced damage in CHON-001 chondrocytes by assessing cellular senescence, OS, and the expression levels of matrix metalloproteinase-13 (MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4. Our results show that Ac2-26 mitigated the reduction of telomerase activity and the exacerbation of cellular senescence induced by TNF-α in CHON-001 chondrocytes. Treatment with TNF-α led to decreased expression of the human telomerase reverse transcriptase gene and increased expression of the telomeric repeat-binding factor 2 gene, which were reversed by Ac2-26 treatment. The TNF-α-induced increases in the gene and protein expressions of p53 and p16 were restored by Ac2-26 in a dose-dependent manner. Additionally, we found that TNF-α caused elevations in the mRNA and protein levels of MMP-13 and ADAMTS-4, which were reduced by Ac2-26 in a dose-dependent fashion. Furthermore, TNF-α triggered the activation of nuclear factor κ-B (NF-κB) by increasing the levels of phosphorylated NF-κB p65 and the luciferase activity of NF-κB. Notably, Ac2-26 alleviated OS by reducing mitochondrial reactive oxygen species levels and promoting the activation of NF-E2-related factor 2 (Nrf2) in TNF-α-challenged CHON-001 chondrocytes. Silencing Nrf2 abolished the Ac2-26-induced activation of NF-κB and cellular senescence in CHON-001 chondrocytes. Collectively, these findings offer new insights into the potential therapeutic use of Ac2-26 for treating OA.

Comparative analysis of treatment outcomes in osteoarthritis knee: integrating physiotherapy and medication versus mono-therapies

Background: Osteoarthritis (OA) of the knee is a prevalent degenerative joint disorder that significantly impacts patients' mobility and quality of life. Effective management of knee OA is crucial to alleviate symptoms and improve daily functioning. This study aims to conduct a comparative analysis of treatment outcomes for knee OA by evaluating three distinct therapeutic approaches: a combination of physiotherapy and medication, physiotherapy alone and medication alone, all supplemented with routine daily activities. Methods: The research involves a cohort of patients diagnosed with knee OA, divided into three groups, each receiving one of the specified treatments. Outcome measures include pain reduction, assessed through the Visual Analog Scale (VAS); functional mobility, evaluated using the Timed Up and Go (TUG) test; and overall quality of life, measured by the Knee Injury and Osteoarthritis Outcome Score (KOOS). Results: Preliminary findings suggest that patients receiving the integrated treatment of physiotherapy and medication show significantly greater improvements in pain relief and functional mobility compared to those undergoing mono-therapies. The combination approach appears to leverage the synergistic effects of both modalities, offering a more comprehensive management strategy. Physiotherapy alone also demonstrates notable benefits in enhancing mobility and reducing pain, while medication primarily provides symptomatic relief. Conclusions: This study underscores the importance of a multidisciplinary approach in treating knee OA, highlighting that integrated treatment plans may offer superior outcomes. These findings aim to inform clinical practice, suggesting that combining physiotherapy with medication can optimize therapeutic efficacy, improve patient quality of life and potentially alter the standard care protocols for knee OA. Further research is warranted to substantiate these results and explore long-term benefits.

Evaluating the Efficacy of Platelet-Rich Plasma in Treating Primary Knee Osteoarthritis: A Prospective Interventional Study.

Knee osteoarthritis (OA) is a prevalent degenerative joint disorder causing pain, stiffness, and reduced function, significantly impacting the quality of life. Current treatments mainly provide symptomatic relief, with limited efficacy in halting disease progression. Platelet-rich plasma (PRP), a biological therapy rich in growth factors, has gained attention as a potential treatment for knee OA due to its regenerative properties. This study evaluates the efficacy of PRP in managing primary knee OA. This prospective interventional study included 100 patients diagnosed with primary knee OA, categorized using the Kellgren-Lawrence grading scale. Leukocyte-reduced PRP was prepared using the double-spin method and injected into the knee joint. The efficacy of PRP was assessed using the Western Ontario and McMaster Universities Arthritis (WOMAC) Index and Visual Analogue Scale (VAS) pain scores at six weeks, three months, and six months post-injection. Statistical analysis was performed using SPSS version 25.0, with significance set at p<0.05. Significant improvements in the WOMAC and VAS scores were observed at all-time points post-PRP injection. The WOMAC score decreased from a baseline of 81.06 to 63.52 at six months (p < 0.001), and the VAS score reduced from 7.53 to 3.09 (p < 0.001). PRP was more effective in patients with lower body mass index (BMI) and less severe OA (Grades 1 and 2). Adverse events were mild, with 18% reporting mild pain or swelling. PRP therapy significantly improves pain and function in patients with primary knee OA, particularly in early-stage disease. The treatment is generally safe, with minor adverse effects. PRP presents a promising non-surgical option, especially for those seeking to delay or avoid knee arthroplasty.

New role of calcium-binding fluorescent dye alizarin complexone in detecting permeability from articular cartilage to subchondral bone.

Osteoarthritis (OA) is a chronic degenerative joint disorder characterized by the progressive deterioration of articular cartilage and concomitant alterations in subchondral bone architecture. However, the precise mechanisms underlying the initiation and progression of OA remains poorly understood. In the present study, we explored whether the calcification in the articular cartilage occurred in the early stage of mouse OA model, generated by the surgery destabilization of the medial meniscus (DMM), via the intra-articular injection of alizarin complexone due to its anionic nature for binding calcium-containing crystals. Although we did not observe the calcification in the articular cartilage of early stage of DMM mice, we unexpectedly identified alizarin complexone had the diffusion capacity for detecting the permeability from the articular cartilage to subchondral bone. Our data showed that the diffusion of alizarin complexone from the articular cartilage to calcified cartilage was greater in the early stage of DMM mice than that in sham controls. Additionally, we observed enhanced penetration of alizarin complexone through the periosteum in DMM mice compared to sham mice. In summary, we developed a novel imaging method that offers a valuable tool for further exploration of biochemical communication underlying OA development. Our findings provided new evidence that increased molecular interactions between the articular cartilage and subchondral bone is involved in the pathogenesis of OA progression.

Exosomes-Shuttled lncRNA SNHG7 by Bone Marrow Mesenchymal Stem Cells Alleviates Osteoarthritis Through Targeting miR-485-5p/FSP1 Axis-Mediated Chondrocytes Ferroptosis and Inflammation.

Osteoarthritis (OA), a degenerative joint disorder, is a major reason of disability in adults. Accumulating evidences have proved that bone marrow mesenchymal stem cells (BMSCs)-carried exosomes play a significant therapeutic effect on OA. However, the precise regulatory network remains unknown. OA and normal cartilage samples were acquired from patients, and chondrocytes were exposed to IL-1β to conduct a cellular OA model. Exosomes prepared from BMSCs were identified using nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Cell viability was determined with CCK-8 assay. Inflammatory injury was assessed by LDH and inflammatory factors (TNF-α and IL-6) using corresponding ELISA kits, respectively. Ferroptosis was evaluated by GSH, MDA and iron levels using corresponding kits, and ROS level with DCFH-DA. The expressions of genes/proteins were determined with RT-qPCR/western bolt. RNA immunoprecipitation and luciferase activity assay were conducted for testing the interactions of small nucleolar RNA host gene 7 (SNHG7)/ferroptosis suppressor protein 1 (FSP1) and miR-485-5p. The expressions of SNHG7 and FSP1 were both reduced in IL-1β-induced chondrocytes and OA cartilage tissues, and there was a positive correlation between them in clinical level. Moreover, SNHG7 was enriched in BMSCs-derived exosomes (BMSCs-Exos) and could be internalized by chondrocytes. Functional analysis illustrated that BMSCs-Exos administration repressed inflammatory injury, oxidative stress and ferroptosis in IL-1β-induced chondrocytes, while these changes were reinforced when SNHG7 was overexpressed in BMSCs-Exos. Notably, FSP1 silencing in chondrocytes abolished the beneficial effects mediated by exosomal SNHG7. Exosomal SNHG7 released from BMSCs inhibited inflammation and ferroptosis in IL-1β-induced chondrocytes through miR-485-5p/FSP1 axis. This work suggested that BMSCs-derived exosomal SNHG7 would be a prospective target for OA treatment.

The Potential of Intra-Articular Therapies in Managing Knee Osteoarthritis: A Systematic Review.

Knee osteoarthritis (KOA) is a common degenerative and progressive joint disorder that negatively influences patients' quality of life. Intra-articular therapies, such as hyaluronic acid (HA) and platelet-rich plasma (PRP), have garnered attention for their potential to manage osteoarthritis OA symptoms effectively. This systematic review aims to identify the effectiveness and safety of HA and PRP treatment modalities in treating KOA. A literature search was conducted across MEDLINE (PubMed), Web of Science Core Collection, and Science Direct Collection Elsevier. Twenty-three randomized controlled trials, cohort studies, and observational studies were included in the review. The selection criteria focused on studies published in English within the last 10 years, involving subjects with KOA treated with intra-articular injections of HA or PRP and reporting on pain, function, or overall treatment efficacy outcomes. The analysis showed that both HA and PRP significantly improve functionality and reduce pain in KOA patients. High molecular weight HA consistently reduced pain and improved joint mobility in various studies. PRP had better long-term outcomes when combined with HA, leading to greater pain reduction and functional improvement. Both therapies had generally favorable safety profiles, with only minor adverse events reported. However, there were potential biases identified across the studies, such as selection, performance, detection, and reporting biases, which impacted the reliability of the results. Intra-articular treatments with HA and PRP show promise in managing knee osteoarthritis, with personalized treatment plans and further research needed to confirm these findings.

Bioengineered chondrocyte membrane-camouflaged anti-ferroptotic drug-loaded liposomes: A highly effective cartilage-targeted drug delivery system for osteoarthritis treatment

Osteoarthritis (OA) is a chronic degenerative joint disorder that severely impacts patients’ quality of life. Despite various drug treatment strategies, achieving effective therapeutic outcomes remains challenging due to the joint’s unique structure, which results in rapid drug clearance through synovial fluid and the dense, avascular cartilage matrix. To address this issue, we developed an innovative nanoplatform utilizing biomimetic cell membrane-coating technology. This bioengineered chondrocyte membrane-camouflaged, anti-ferroptotic, drug-loaded system enhances cartilage penetration, prolongs drug retention, and provides targeted therapy. As a nanovehicle, it targets chondrocytes through membrane fusion, allowing rapid penetration and mitigating OA progression. In vitro experiments show that this nanocarrier alleviates iron homeostasis imbalance and suppresses lipid peroxidation, helping ameliorate metabolic disorders in chondrocytes and addressing multiple pathological processes triggered by ferroptosis. In vivo results further suggest that this “Trojan Horse” strategy extends drug retention in joints and improves therapeutic efficacy. This study presents a potential universal nanoplatform comprising bioengineered chondrocyte membrane-coated liposomes for highly effective cartilage-targeted drug delivery in OA treatment.

Exploring the impact of curcumin on osteoarthritis symptomatology: correlations and insights from a Bulgarian cohort.

Osteoarthritis is a prevalent degenerative joint disorder associated with pain and functional impairment. Curcumin, a natural anti-inflammatory compound, has garnered attention for its potential therapeutic benefits in osteoarthritis management.

An in-depth study to fine-tune the hyperparameters of pre-trained transfer learning models with state-of-the-art optimization methods: Osteoarthritis severity classification with optimized architectures

Discrete & continuous optimization constitutes a challenging task and generally rises as an NP-hard problem. In the literature, as a derivative of this type of optimization issue, hyperparameter optimization of transfer learning (TL) architectures is not efficiently analyzed as a detailed survey in the literature. In this paper, the optimized TL-based models are effectively examined to handle this issue which constitutes the main aim of our study. For evaluation, knee osteoarthritis (KOA – a chronic degenerative joint disorder) dataset is handled to perform two challenging classification tasks which reveal the second aim of our study, i.e. binary- and multi-categorizations on KOA X-ray images. To fine-tune the hyperparameters of TL models, state-of-the-art optimization methods are chosen and compared on this competitive – NP-hard problem. Sixteen optimized architectures are designed using four efficient optimization methods (ASPSO, CDW-PSO, CSA, MSGO) and four oft-used TL models (MobileNetV2, ResNet18, ResNet50, ShuffleNet) to classify the X-ray KOA images. Regarding the experiments on both categorization tasks, the MSGO algorithm arises as more robust to be considered for hyperparameter tuning of TL-based models by achieving reliable performance. In addition, it's seen that MobileNetV2 and ResNet-based models come to the forefront for X-ray imaging-based classification by achieving high accuracy rates due to the usage of residual blocks. Consequently, in terms of mean accuracy, ResNet50-MSGO and MobileNetV2-CSA respectively record 93.15 % and 93.29 % success rates on multiclass categorization, while ResNet18-CDW-PSO and MobileNetV2-MSGO provide the same highest score of 99.43 % on binary categorization.

Cinnamaldehyde-Treated Bone Marrow Mesenchymal-Stem-Cell-Derived Exosomes via Aqueous Two-Phase System Attenuate IL-1β-Induced Inflammation and Catabolism via Modulation of Proinflammatory Signaling Pathways.

Osteoarthritis (OA) is a degenerative joint disorder that is distinguished by inflammation and chronic cartilage damage. Interleukin-1β (IL-1β) is a proinflammatory cytokine that plays an important role in the catabolic processes that underlie the pathogenesis of OA. In this study, we investigate the therapeutic efficacy of exosomes derived from untreated bone-marrow-derived mesenchymal stem cells (BMMSC-Exo) and those treated with cinnamaldehyde (BMMSC-CA-Exo) for preventing the in vitro catabolic effects of IL-1β on chondrocytes. We stimulated chondrocytes with IL-1β to mimic the inflammatory microenvironment of OA. We then treated these chondrocytes with BMMSC-Exo and BMMSC-CA-Exo isolated via an aqueous two-phase system and evaluated their effects on the key cellular processes using molecular techniques. Our findings revealed that treatment with BMMSC-Exo reduces the catabolic effects of IL-1β on chondrocytes and alleviates inflammation. However, further studies directly comparing treatments with BMMSC-Exo and BMMSC-CA-Exo are needed to determine if CA preconditioning can provide additional anti-inflammatory benefits to the exosomes beyond those of CA preconditioning or treatment with regular BMMSC-Exo. Through a comprehensive molecular analysis, we elucidated the regulatory mechanisms underlying this protective effect. We found a significant downregulation of proinflammatory signaling pathways in exosome-infected chondrocytes, suggesting the potential modulation of the NF-κB and MAPK signaling cascades. Furthermore, our study identified the molecular cargo of BMMSC-Exo and BMMSC-CA-Exo, determining the key molecules, such as anti-inflammatory cytokines and cartilage-associated factors, that may contribute to their acquisition of chondroprotective properties. In summary, BMMSC-Exo and BMMSC-CA-Exo exhibit the potential as therapeutic agents for OA by antagonizing the in vitro catabolic effects of IL-1β on chondrocytes. The regulation of the proinflammatory signaling pathways and bioactive molecules delivered by the exosomes suggests a multifaceted mechanism of action. These findings highlight the need for further investigation into exosome-based therapies for OA and joint-related diseases.

The Association of MMP-2, MMP-9, and MMP-13 Gene Polymorphisms With Knee Osteoarthritis in the Greek Population.

Introduction Primary knee osteoarthritis (OA) is a multifactorial degenerative joint disorder characterized by articular cartilage degradation. Matrix metalloproteinases (MMPs) have been reported to play a vital role in OA pathogenesis, significantly contributing to extracellular matrix (ECM) catabolism. The purpose of this study is to investigate the association of MMP-2 -1575G/A (rs243866), MMP-9 836A/G (rs17576), and MMP-13 -77A/G (rs2252070) gene polymorphisms with knee OA in the Greek population. Methods One hundred patients (24% males, mean age: 68.3 years) with primary knee OA were included in the study along with 100 controls (47% males, mean age: 65.2 years). Genotypes were identified through polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) technique. Allelic and genotypic frequencies were compared between patients and controls. Results The MMP-13 -77A/G polymorphism was significantly associated with knee OA in the crude analysis (P = 0.008). After binary logistic regression analysis, the dominant model of the MMP-13-77A/G (AG + GG versus AA) was found to be associated with increased risk for knee OA (odds ratio (OR) = 2.290, 95% confidence interval (95%CI) = 1.059-4.949, P= 0.035).Compared to the A allele, the G allele in the MMP-13rs2252070 locus was a predictive factor for knee OA (OR = 2.351, 95%CI = 1.134-4.874, P= 0.022). No significant associations were detected for the MMP-2 -1575G/A and MMP-9 836A/G polymorphisms (P > 0.05). Conclusions The present study shows that the MMP-2 -1575G/A and MMP-9 836A/G polymorphisms are not significantly associated with primary knee OA in the Greek population. The MMP-13 -77A/G was found to be a significant risk factor for knee OA in the Greek population. Additional research is needed to verify this association in larger and different populations, in different joints, to elucidate the role of this single nucleotide polymorphism (SNP) in OA pathogenesis.

Three-gene signature revealing the dynamics of lymphocyte infiltration in subchondral bone during osteoarthritis progression

Osteoarthritis (OA), a degenerative joint disorder, has an unclear immune infiltration mechanism in subchondral bone (SCB). Thus, this study aims to discern immune infiltration variations in SCB between early- and late-stages of OA and identify pertinent biomarkers. Utilizing the GSE515188 bulk-seq profile from the Gene Expression Omnibus database, we performed single-sample gene-set enrichment analysis alongside weighted gene co-expression network analysis to identify key cells and immune-related genes (IRGs) involved in SCB at both stages. At the meanwhile, differentially expressed genes (DEGs) were identified in the same dataset and intersected with IRGs to find IR-DEGs. Protein-protein interaction network and enrichment analyses and further gene filtering using LASSO regression led to the discovery of potential biomarkers, which were then validated by ROC curve analysis, single-cell RNA sequencing, qRT-PCR, western blot and immunofluorescence. ScRNA-seq analysis using GSE196678, qRT-PCR, western blot and immunofluorescence results confirmed the upregulation of their expression levels in early-stage OA SCB samples. Our comprehensive analysis revealed lymphocytes infiltration as a major feature in early OA SCB. A total of 13 IR-DEGs were identified, showing significant enrichment in T- or B-cell activation pathways. Three of them (CD247, POU2AF1, and TNFRSF13B) were selected via the LASSO regression analysis, and results from the ROC curve analyses indicated the diagnostic efficacy of these 3 genes as biomarkers. These findings may aid in investigating the mechanisms of SCB immune infiltration in OA, stratifying OA progression, and identifying relevant therapeutic targets.

α-Ketoglutarate alleviates osteoarthritis by inhibiting ferroptosis via the ETV4/SLC7A11/GPX4 signaling pathway

Osteoarthritis (OA) is the most common degenerative joint disorder that causes disability in aged individuals, caused by functional and structural alterations of the knee joint. To investigate whether metabolic drivers might be harnessed to promote cartilage repair, a liquid chromatography–mass spectrometry (LC–MS) untargeted metabolomics approach was carried out to screen serum biomarkers in osteoarthritic rats. Based on the correlation analyses, α-ketoglutarate (α-KG) has been demonstrated to have antioxidant and anti-inflammatory properties in various diseases. These properties make α-KG a prime candidate for further investigation of OA. Experimental results indicate that α-KG significantly inhibited H2O2-induced cartilage cell matrix degradation and apoptosis, reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), increased superoxide dismutase (SOD) and glutathione (GSH)/glutathione disulfide (GSSG) levels, and upregulated the expression of ETV4, SLC7A11 and GPX4. Further mechanistic studies observed that α-KG, like Ferrostatin-1 (Fer-1), effectively alleviated Erastin-induced apoptosis and ECM degradation. α-KG and Fer-1 upregulated ETV4, SLC7A11, and GPX4 at the mRNA and protein levels, decreased ferrous ion (Fe2+) accumulation, and preserved mitochondrial membrane potential (MMP) in ATDC5 cells. In vivo, α-KG treatment inhibited ferroptosis in OA rats by activating the ETV4/SLC7A11/GPX4 pathway. Thus, these findings indicate that α-KG inhibits ferroptosis via the ETV4/SLC7A11/GPX4 signaling pathway, thereby alleviating OA. These observations suggest that α-KG exhibits potential therapeutic properties for the treatment and prevention of OA, thereby having potential clinical applications in the future.

Donor Sites and Harvesting Techniques Affect miRNA Cargos of Extracellular Vesicles Released by Human Adipose-Derived Mesenchymal Stromal Cells.

Osteoarthritis (OA) is a degenerative joint disorder characterized by the progressive deterioration of articular cartilage driven and sustained by catabolic and inflammatory processes that lead to pain and functional impairment. Adipose-derived stem cells (ASCs) have emerged as a promising therapeutic strategy for OA due to their regenerative potential, which mainly relies on the adaptive release of paracrine molecules that are soluble or encapsulated in extracellular vesicles (EVs). The biological effects of EVs specifically depend on their cargo; in particular, microRNAs (miRNAs) can specifically modulate target cell function through gene expression regulation. This study aimed to investigate the impact of collection site (abdominal vs. peri-trochanteric adipose tissue) and collection method (surgical excision vs. lipoaspiration) on the miRNAs profile in ASC-derived EVs and their potential implications for OA therapy. EV-miRNA cargo profiles from ASCs of different origins were compared. An extensive bioinformatics search through experimentally validated and OA-related targets, pathways, and tissues was conducted. Several miRNAs involved in the restoration of cartilage homeostasis and in immunomodulation were identified in all ASC types. However, EV-miRNA expression profiles were affected by both the tissue-harvesting site and procedure, leading to peculiar characteristics for each type. Our results suggest that adipose-tissue-harvesting techniques and the anatomical site of origin influence the therapeutic efficacy of ASC-EVs for tissue-specific regenerative therapies in OA, which warrants further investigation.

Attenuation of osteoarthritis progression via locoregional delivery of Klotho-expressing plasmid DNA and Tanshinon IIA through a stem cell-homing hydrogel

BackgroundOsteoarthritis (OA) is an aging-related degenerative joint disorder marked by joint discomfort and rigidity. Senescent chondrocytes release pro-inflammatory cytokines and extracellular matrix-degrading proteins, creating an inflammatory microenvironment that hinders chondrogenesis and accelerates matrix degradation. Targeting of senescent chondrocytes may be a promising approach for the treatment of OA. Herein, we describe the engineering of an injectable peptide-hydrogel conjugating a stem cell–homing peptide PFSSTKT for carrying plasmid DNA-laden nanoparticles and Tanshinon IIA (pPNP + TIIA@PFS) that was designed to attenuate OA progression by improving the senescent microenvironment and fostering cartilage regeneration.ResultsSpecifically, pPNP + TIIA@PFS elevates the concentration of the anti-aging protein Klotho and blocks the transmission of senescence signals to adjacent healthy chondrocytes, significantly mitigating chondrocyte senescence and enhancing cartilage integrity. Additionally, pPNP + TIIA@PFS recruit bone mesenchymal stem cells and directs their subsequent differentiation into chondrocytes, achieving satisfactory chondrogenesis. In surgically induced OA model rats, the application of pPNP + TIIA@PFS results in reduced osteophyte formation and attenuation of articular cartilage degeneration.ConclusionsOverall, this study introduces a novel approach for the alleviation of OA progression, offering a foundation for potential clinical translation in OA therapy.

Objectively assessing visual analogue scale of knee osteoarthritis pain using thermal imaging

Knee osteoarthritis (KOA) is a common degenerative joint disorder that significantly deteriorates the quality of life for affected patients, primarily through the symptom of knee pain. In this study, we developed a machine learning methodology that integrates infrared thermographic technology with health data to objectively evaluate the Visual Analogue Scale (VAS) scores for knee pain in patients suffering from KOA. We preprocessed thermographic data from two healthcare centers by removing background noise and extracting Regions of Interest (ROI), which allowed us to capture image features. These were then merged with patient health data to build a comprehensive feature set. We employed various regression models to predict the VAS scores. The results indicate that the XGBoost model, using a 7:3 training-to-testing ratio, outperformed other models across several evaluation metrics. This study confirms the practicality and effectiveness of using thermographic imaging and machine learning for assessing knee pain, providing a new supportive tool for the management of pain in KOA and potentially increasing the objectivity of clinical assessments. The research is primarily focused on the middle-aged and elderly populations. In the future, we plan to extend the use of this technology to monitor risk factors in children’s knees, with the goal of improving their long-term quality of life and enhancing the overall well-being of the population.