Chronic Joint Disease Research Articles

Combined detection of serum CTX-II and C2C in a rat model of ACLT-induced osteoarthritis.

Osteoarthritis (OA) is a chronic degenerative bone and joint disease that often occurs in aging animals. Currently, there are still no biomarkers that can effectively diagnose OA in the early stage. To identify possible biomarkers, here we examined changes in the expression of C-telopeptide fragments of type II collagen (CTX-II) and collagenase generated carboxy-terminal neoepitope of type II collagen (C2C) in serum at different time points in an anterior cruciate ligament transection (ACLT)-induced rat OA model. The serum levels of CTX-II and C2C, and the OARSI score in the ACLT group were increased from week two until the end of the experiment. The AUC of the combined biomarkers was higher than that of CTX-II or C2C alone. Moreover, serum levels of CTX-II and C2C were positively correlated with the OARSI score. The results suggest that the combined detection of serum CTX-II and C2C concentrations may have potential for assessing and diagnosing OA at early stages.

The effects of mesenchymal stem cells-derived exosomes in rheumatoid arthritis: a review.

Rheumatoid arthritis (RA) is a most common chronic joint disease belonging to inflammatory autoimmune disease. The pathology of the disease is characterised by the infiltration and proliferation of fibroblast like synoviocytes (FLSs) and the destruction of the bone and cartilage matrix, which leads to joint dysfunction and even deformity.In recent years, an increasing number of studies have shown that MSCs have immunosuppressive properties and have been demonstrated in a variety of disease. Exosomes serve as carriers that mediate intercellular material transfer and information exchange and contain a variety of biologically active components such as proteins, lipids, and nucleic acids. Mesenchymal stem cell-derived exosomes (MSCs-Exos) play a regulatory role by carrying bioactive substances from the parental cells. Exos-derived from MSCs of different origins can modulate several pathological processes, such as immune inflammatory response, improvement of bone metabolism. In this research, we reviewed the current major pathogenesis of RA and explored the important role of MSCs-Exos in this disease. To be more precise, we summarised the effects of different MSCs-Exos on the pathomechanisms of RA, with a view to providing guidance and reference for future studies.

Exploration of effective biomarkers and infiltrating Immune cells in Osteoarthritis based on bioinformatics analysis

Osteoarthritis (OA) is a multi-factorial chronic joint disease mainly identified by synovial inflammation, cartilage damage, and degeneration. Our study applied bioinformatics analysis to uncover the immunity in OA and tried to explore the underlying immune-related molecular mechanism. First, OA-related gene-expression profiling data were retrieved from GEO database. Then, we analysed a series of datadata with using the xCell algorithm, GEO2R, enrichment analysis of SangerBox website, CytoHubba, ROC logistic regression and correlation analysis. Finally, Nine infiltrating immune cells with differential abundance between OA and normal samples were obtained. There were 42 IODEGs in OA, and their functions were associated with immune cells and corresponding biological processes. Moreover, 5 hub genes, including GREM1, NRP1, VEGFA, FYN and IL6R, were identified. Correlation analysis demonstrated that NRP1 was negatively associated with NKT cells, NRP1 and GREM1 were positively associated with aDC, VEGFA was positively associated with CD8+ naïve T cells, while VEGFA, FYN and IL6R were negatively associated with Macrophages M1. The 5 hub genes could be employed as effective diagnostic biomarkers for OA. In addition, they may participate in OA pathogenesis via interactions with infiltrating immune cells.

The Protective Effect of Selenium Nanoparticles in Osteoarthritis: In vitro and in vivo Studies.

Osteoarthritis (OA) is a common chronic joint disease characterized by articular cartilage degeneration. OA usually manifests as joint pain, limited mobility, and joint effusion. Currently, the primary OA treatment is non-steroidal anti-inflammatory drugs (NSAIDs). Although they can alleviate the disease's clinical symptoms and signs, the drugs have some side effects. Selenium nanoparticles (SeNPs) may be an alternative to relieve OA symptoms. We confirmed the anti-inflammatory effect of selenium nanoparticles (SeNPs) in vitro and in vivo experiments for OA disease in this study. In vitro experiments, we found that SeNPs could significantly reduce the expression of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), the major inflammatory factors, and had significant anti-inflammatory and anti-arthritic effects. SeNPs can inhibit reactive oxygen species (ROS) production and increased glutathione peroxidase (GPx) activity in interleukin-1beta (IL-1β)-stimulated cells. Additionally, SeNPs down-regulated matrix metalloproteinase-13 (MMP-13) and thrombospondin motifs 5 (ADAMTS-5) expressions, while up-regulated type II collagen (COL-2) and aggrecan (ACAN) expressions stimulated by IL-1β. The findings also indicated that SeNPs may exert their effects through suppressing the NF-κB p65 and p38/MAPK pathways. In vivo experiments, the prevention of OA development brought on by SeNPs was demonstrated using a DMM model. Our results suggest that SeNPs may be a potential anti-inflammatory agent for treating OA.

Monotropein attenuates apoptosis and pyroptosis in chondrocytes and alleviates osteoarthritis progression in mice

BackgroundOsteoarthritis (OA) is a chronic degenerative joint disease characterized by loss of joint function, which seriously reduces the quality of life of the elderly and imposes a heavy socioeconomic burden worldwide. Monotropein (MON), the main active ingredient of Morinda officinalis F.C. How, has exhibited therapeutic effects in different disease models. However, its potential effects on chondrocytes in an arthritic model remain unclear. This study aimed to evaluate the effects of MON in chondrocytes and a mouse model of OA, and explore the potential mechanisms. Materials and methodsMurine primary chondrocytes were pretreated with 10 ng/ml interleukin (IL)-1β for 24 h to establish an in vitro model of OA, and then treated with different concentrations of MON (0, 25, 50 and 100 μM) for 24 h. The proliferation of the chondrocytes was assayed using ethynyl-deoxyuridine (EdU) staining. Immunofluorescence staining, western blotting and TUNEL staining were performed to assess the effects of MON on cartilage matrix degradation, apoptosis and pyroptosis. The mouse model of OA was constructed by surgical destabilization of the medial meniscus (DMM), and the animals were randomly divided into the sham-operated, OA and OA + MON groups. Following OA induction, the mice were given intraarticular injection of 100 μM MON or equal volume of normal saline twice a week for 8 weeks. The effects of MON on cartilage matrix degradation, apoptosis and pyroptosis were assessed as indicated. ResultsMON significantly accelerated the proliferation of chondrocytes, and inhibited cartilage matrix degradation, apoptosis and pyroptosis in the IL-1β-stimulated cells by blocking the nuclear factor-kappa B (NF-κB) signaling pathway. In the mouse model as well, MON treatment alleviated OA progression and promoted cartilage repair by inhibiting cartilage matrix degradation, and chondrocyte apoptosis and pyroptosis through the inactivation of the NF-κB signaling pathway. Furthermore, the MON-treated arthritic mice exhibited better articular tissue morphology and lower OARSI scores. ConclusionsMON alleviated OA progression by inhibiting cartilage matrix degradation, and the apoptosis and pyroptosis of chondrocytes via NF-κB pathway inactivation, and is a promising alternative for the treatment of OA.

Innovation in Targeted Intra-articular Therapies for Osteoarthritis

Osteoarthritis is the most common chronic joint disease characterized by progressive damage to the joints, leading to pain and loss of function. There is currently no cure or disease-modifying therapy for osteoarthritis. Hence, the increasing disease prevalence linked with ageing and obesity represents a substantial socio-economic burden. Intra-articular therapy by injection of drugs into affected joints can optimize local drug bioavailability, while reducing risks of systemic toxicity, a concern in an ageing patient population. In this review, we investigate the current landscape of intra-articular drug therapies for osteoarthritis, including established approaches and those in clinical development. We performed a literature review using PubMed, complemented with a search for clinical trials using the ClinicalTrials.gov repository. Additionally, conference abstracts and presentations were identified and systematic snowballing was applied. Identified drugs were divided into several groups by main mechanism of action, and include drugs that reduce inflammation (anti-inflammatory), drugs aiming to prevent or reverse structural damage (structure modifying), drugs that aim to reduce the pain, and other drugs with a specific target. Most studies have been performed for osteoarthritis of the knee, a joint that is easily accessible for intra-articular treatments. Optimal therapy would provide symptomatic relief, while preventing further damage to the joint. The field of intra-articular drug therapies for osteoarthritis is rapidly evolving with clear challenges identified: definition of relevant outcome measures, optimization of clinical trial set-ups, and dealing with placebo responses. While many uncertainties persist, it appears that the innovation in drug development and improved clinical trial set-up may finally deliver successful therapies for this important disease.

Possible immune mechanisms initiated by 7-ketocholesterol that contribute to synovial oxidative stress and inflammation

Osteoarthritis (OA) is a chronic joint disease caused by both mechanical damage and metabolic factors, which intertwine in their pathogenetic pathways. We hypothesise that the oxidised cholesterol derivative, 7-ketocholesterol (7-KCh), represents a danger signal in the synovia of patients with OA and promotes low-grade inflammation. The study would aim to elucidate the possible immune mechanisms initiated by 7-KCh that contribute to oxidative stress and inflammation in the synovia and synovial CD68+ cells, which are mostly macrophages. The polarisation of synovial CD68+ cells, their tissue distribution in relation to T and natural killer (NK) cells, and the influence of 7-KCh on the phenotype and intracellular cytokine and chemokine production in suspension is worth analysing. We envisage that this research would contribute to a better understanding of the biology of CD68+ macrophages influenced by 7-KCh and encourage the development of therapeutic approaches based on directing macrophage polarisation.

HUCMSCS-DERIVED EXOSOMES SUPPRESS OSTEOARTHRITIS IN RABBITS THROUGH INHIBITING CCL2

Osteoarthritis (OA), the most prevalent chronic joint disease, represents a relevant social and economic burden worldwide. Human umbilical cord mesenchymal stem cells (HUCMSCs) have been used for injection into the joint cavity to treat OA. The aim of this article is to clarify whether Huc-MSCs derived exosomes could inhibit the progression of OA and the mechanism in this process.A rabbit OA model was established by the transection of the anterior cruciate ligament. The effects of HUCMSCs or exosomes derived from HUCMSCs on repairing articular cartilage of knee osteoarthritis was examined by micro-CT. Immunohistochemical experiments were used to confirm the expression of relevant inflammatory molecules in OA. In vitro experiments, Transwell assay was used to assess the migration of macrophages induced by TNF-a.Results showed that a large number of macrophages migrated in arthcular cavity in OA model in vivo, while local injection of HUCMSCs and exosomes did repair the articular cartilage. Immunohistochemical results suggested that the expression of CCL2 and CD68 in the OA rabbit model increased significantly, but was significantly reduced by HUCMSCs or exosomes. Transwell assay showed that both HUCMSCs and exosomes can effectively inhibit the migration of macrophage.In conclusion, the exosomes derived by HUCMSCs might might rescue cartilage defects in rabbit through its anti-inflammatory effects through inhibiting CCL2.

Osteoarthritis, part of life or a curable disease? A bird's-eye view.

Osteoarthritis (OA) is a chronic joint disease caused by disruption of joint homeostasis by a variety of systemic and biomechanical factors. The disease is characterized by degradation of cartilage and other joint tissues, and low-grade inflammation which may result in pain, reduced function, and disability. The disease appears to have ancient origins, with findings of OA recognized in fossilized bones from birdlike dinosaurs living some 130 million years ago. Today, the burden of OA in the world's population is steadily increasing due to aging and often rising rates of obesity. Structural findings, indicative of the disease, are also frequent in asymptomatic persons, which make the distinction between disease and normal aging sometimes challenging. OA is frequently associated with comorbidity in the form of obesity, cardiovascular disease, and depressive symptoms. The current management and treatments largely rely on contextual factors, and the actual effects of the intended therapeutic element of today's interventions are minor. The different mechanistic pathways (endotypes) and clinical characteristics (phenotypes) of OA make the development of disease-modifying treatments challenging. Current development of drug candidates, aimed to restore joint homeostasis, is mainly targeting either inhibition of catabolic factors or stimulation of anabolic factors. However, there is yet no breakthrough in stage III clinical trials. Earlier diagnosis, better knowledge of endotypes-for example, by new insights into soluble biomarkers, and compositional imaging-and more careful selection of patients into clinical trials are possible tools to aid development of future therapies.

Nursing Actions after Hip Total Joint Replacement Surgery

The joint replacement surgery is one of the greatest achievements of medicine these days. They are one of the most effective surgical interventions, performed recently, both in medical and economic terms [1].
 Every year in Lithuania as well as worldwide, the number of joint replacement surgeries is constantly increasing. This is influenced by the ageing population as well as the increasing number of people with chronic degenerative joint diseases [2].
 Despite the fact that hip, knee total joint replacement surgeries have become routine orthopedic surgeries, however, special care and nursing by medical employees are required during the postoperative period.
 The purpose of the research. To analyze nursing actions after the hip total joint replacement surgery. A quantitative survey has been performed by the questionnaire method; its participants were nurses, working in health care institutions of Utena City.
 The research revealed that the nurses shall assess the patient's general condition, his/her vital indicators, the wound, the drains and solve theproblems that have occurred.

Daurisoline attenuates H2O2-induced chondrocyte autophagy by activating the PI3K/Akt/mTOR signaling pathway

BackgroundOsteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degeneration and intra-articular inflammation. Daurisoline (DAS) is an isoquinoline alkaloid isolated from Rhizoma Menispermi, whose antitumor and anti-inflammatory pharmacological effects have been demonstrated, but the effects of DAS on OA have rarely been researched. In this study, we aimed to explore the potential role of DAS in OA and its partial mechanism.Materials and methodsThe cytotoxicity of H2O2 and DAS toward chondrocytes was detected by the Cell Counting Kit-8 assay. Safranin O staining was used to detect chondrocyte phenotype changes. Cell apoptosis was measured by both flow cytometry and quantitative analysis of the protein levels of the apoptosis-related factors Bax, Bcl-2 and cleaved caspase-3 by western blot. Western blotting and immunofluorescence were used to assess the expression of the autophagy-related proteins LC3, Beclin-1 and p62. In addition, key signal pathway targets and matrix-degrading indicators were measured by western blot.ResultsOur results indicated that H2O2 induced human chondrocyte apoptosis and activated autophagy in a dose-dependent manner. DAS treatment dose-dependently reversed the expression of apoptosis-related proteins (Bax, Bcl-2 and cleaved caspase3) and the apoptosis rate induced by H2O2. Western blot and immunofluorescence analyses showed that DAS decreased the H2O2-induced upregulation of the autophagy marker Beclin-1 and the LC3 II/LC3 I ratio and upregulated the p62 protein level. Mechanistically, DAS inhibited autophagy through the activation of the classical PI3K/AKT/mTOR signaling pathway and protected chondrocytes from apoptosis. In addition, DAS alleviated the H2O2-induced degradation of type II collagen and the high expression of matrix metalloproteinase 3 (MMP3) and MMP13.ConclusionOur research demonstrated that DAS alleviated chondrocyte autophagy caused by H2O2 through activation of the PI3K/AKT/mTOR signaling pathway and protected chondrocytes from apoptosis and matrix degradation. In conclusion, these findings suggest that DAS may serve as a promising therapeutic strategy for OA.

Knowledge and Awareness Regarding Osteoarthritis and Its Factors in Hail Region, Saudi Arabia.

Objectives Osteoarthritis (OA) is a common chronic degenerative joint disease linked to age, joint overuse abnormalities, and previous trauma. This research aims to assess the awareness levels, as well as the knowledge gap and misconceptions, about OA and its risk factors among the general population in Hail, Saudi Arabia. Methods The research adopted an observational cross-sectional method. Participants from Hail, Saudi Arabia, were recruited and then interviewed between 1 April and 15 July 2022. Adult males and females aged 18 or more were recruited via an online questionnaire using a Google Form link, inviting them to take part in a study concerning their knowledge of OA.Thequestionnaire was split into three sections. The first section covered demographic data, the second section contained general knowledge regarding OA, and the third section was made up of a 20-item quiz. The collected data was reviewed and then analyzed using the Statistical Package for Social Sciences (SPSS) Version 21 (IBM Corp., Armonk, NY, USA). The statistical methods employed were all two-tailed, with an alpha level of 0.05 considered significant if the P value was less than, or equal to, 0.05. Results Nine hundred six (906) eligible respondents completed the questionnaire. Participants ranged from 18 to 65 in age. More than 66% were female, while 77.5% had a university level of education or above. 13.6% had been diagnosed with OA. Overall, 40.9% of the study participants demonstrated a good knowledge level regarding OA, while 59.1% showed a poor knowledge level. Conclusion The study revealed that the awareness and knowledge levels of the general population in Hail about OA are unsatisfactory. Efforts are recommended to increase the awareness and knowledge of the population through public education, which in turn can lead to a reduction in risk factors and improved early detection of the disease.

Functional Mechanism of Mesenchymal Stem Cell-Derived Exosomes in Articular Cartilage Regeneration

As the aging of the population, a chronic degenerative joint disease - Osteoarthritis (OA), its incidence and severity are increasing. Compared with cells, the immunogenicity of the exon is low and the immunomodulatory performance is excellent. Various types of mesenchymal stem cell-derived exosomes (MSC-EXOs) are now being used to treat cartilage injury and disease as target drugs or delivery vehicles. A thorough examination of the existing evidence is required in light of the emerging evidence on the effective mechanism and method of MSC-EXOs in OA. This article reviews the specific mechanism and latest research progress of MSCs derived exosomes in OA treatment. It mainly summarizes three mechanisms of action of exosomes: a. Enhancing extracellular matrix (ECM) and preventing cartilage degradation; b. Promoting chondrocyte migration, proliferation, migration, and inhibiting chondrocyte apoptosis, c. Influencing immune protection or immune destruction signals. In addition, the difficulties of exosomes in the clinical treatment of OA are briefly reviewed, with the hope of providing ideas for developing biomaterials scaffolds and clinical treatment of MSC-EXOs.

The effect of allyl isothiocyanate on chondrocyte phenotype is matrix stiffness-dependent: Possible involvement of TRPA1 activation.

Osteoarthritis (OA) is a chronic joint disease with increasing prevalence. Chondrocytes (CHs) are highly differentiated end-stage cells with a secretory phenotype that keeps the extracellular matrix (ECM) balanced and the cartilage environment stable. Osteoarthritis dedifferentiation causes cartilage matrix breakdown, accounting for one of the key pathogenesis of osteoarthritis. Recently, the activation of transient receptor potential ankyrin 1 (TRPA1) was claimed to be a risk factor in osteoarthritis by causing inflammation and extracellular matrix degradation. However, the underlying mechanism is still unknown. Due to its mechanosensitive property, we speculated that the role of TRPA1 activation during osteoarthritis is matrix stiffness-dependent. In this study, we cultured the chondrocytes from patients with osteoarthritis on stiff vs. soft substrates, treated them with allyl isothiocyanate (AITC), a transient receptor potential ankyrin 1 agonist, and compared the chondrogenic phenotype, containing cell shape, F-actin cytoskeleton, vinculin, synthesized collagen profiles and their transcriptional regulatory factor, and inflammation-related interleukins. The data suggest that allyl isothiocyanate treatment activates transient receptor potential ankyrin 1 and results in both positive and harmful effects on chondrocytes. In addition, a softer matrix could help enhance the positive effects and alleviate the harmful ones. Thus, the effect of allyl isothiocyanate on chondrocytes is conditionally controllable, which could be associated with transient receptor potential ankyrin 1 activation, and is a promising strategy for osteoarthritis treatment.

The Bcr-Abl inhibitor DCC-2036 inhibits necroptosis and ameliorates osteoarthritis by targeting RIPK1 and RIPK3 kinases

Osteoarthritis (OA) is a chronic progressive degenerative joint disease. Owing to its complex pathogenesis, OA treatment is typically challenging. Necroptosis is a form of programmed cell death mainly mediated by the serine/threonine kinases, RIPK1 and RIPK3, and mixed lineage kinase-like domain (MLKL). In this study, we found that the multi-targeted kinase inhibitor DCC-2036 can inhibit TSZ (TNF-α, Smac mimetic, and z-VAD-FMK)-induced necroptosis of chondrocytes and synovial fibroblast cells (SFs). In addition, we found that oral DCC-2036 inhibited chondrocyte damage in a rat model of OA induced by intra-articular injection of monosodium iodoacetate (MIA). A mechanistic study showed that DCC-2036 directly inhibited the activities of RIPK1 and RIPK3 kinases to block necroptosis, inhibiting the inflammatory response and protecting chondrocytes. In summary, our research suggests that DCC-2036, a new necroptosis inhibitor targeting RIPK1 and RIPK3 kinase activity, may be useful for the clinical treatment of OA and provides a new direction for the research and treatment of OA.

Global Research Hotspots and Trends of Physical Activity in Knee Osteoarthritis: A Bibliometric Analysis.

BACKGROUND Knee osteoarthritis (OA) is a chronic joint disease characterized by pain, swelling, and limited knee activity. Numerous studies have reported the efficacy and mechanism of physical activity in patients with knee OA. However, bibliometric analyses of physical activity and knee OA are rare. This study aimed to discuss the hotspots, frontiers, and trends in physical activity and knee OA research using bibliometric methods to provide valuable information for future research. MATERIAL AND METHODS Relevant literature was obtained from the Web of Science Core Collection database from 2000 to 2021. English-language articles and reviews were selected. CiteSpace (6.1.R2), a bibliometric analytical tool, was used to analyze the countries, institutions, journals, authors, keywords, and references. RESULTS A total of 860 papers were obtained. Publications and citations have increased over the years. The most productive country, institution, author, and journal were USA, the University of Melbourne, Bennell KL, and Osteoarthritis and Cartilage. The author and journal with the most citations were Fransen M and Osteoarthritis and Cartilage. McAlindon TE et al's paper had the most citations and the strongest burst. Two references for the latest bursts were published by Fransen M et al. and Bartholdy C et al. The top 4 keywords were "hip," "knee osteoarthritis," "pain," and "older adult." The keywords for the latest burst were "guideline" and "risk." CONCLUSIONS Over the past 2 decades, research on physical activity in knee OA has received increasing attention. This study identified research hotspots and development trends, providing meaningful information for researchers.

Equine osteoarthritis modifies fatty acid signatures in synovial fluid and its extracellular vesicles

BackgroundIndividual fatty acids (FAs) and their derivatives (lipid mediators) with pro-inflammatory or dual anti-inflammatory and pro-resolving properties have potential to influence the health of joint tissues. Osteoarthritis (OA) is an age-associated chronic joint disease that can be featured with altered FA composition in the synovial fluid (SF) of human patients. The counts and cargo of extracellular vesicles (EVs), membrane-bound particles released by synovial joint cells and transporting bioactive lipids, can also be modified by OA. The detailed FA signatures of SF and its EVs have remained unexplored in the horse — a well-recognized veterinary model for OA research.MethodsThe aim of the present study was to compare the FA profiles in equine SF and its ultracentrifuged EV fraction between control, contralateral, and OA metacarpophalangeal joints (n = 8/group). The FA profiles of total lipids were determined by gas chromatography and the data compared with univariate and multivariate analyses.ResultsThe data revealed distinct FA profiles in SF and its EV-enriched pellet that were modified by naturally occurring equine OA. Regarding SFs, linoleic acid (generalized linear model, p = 0.0006), myristic acid (p = 0.003), palmitoleic acid (p < 0.0005), and n-3/n-6 polyunsaturated FA ratio (p < 0.0005) were among the important variables that separated OA from control samples. In EV-enriched pellets, saturated FAs palmitic acid (p = 0.020), stearic acid (p = 0.002), and behenic acid (p = 0.003) indicated OA. The observed FA modifications are potentially detrimental and could contribute to inflammatory processes and cartilage degradation in OA.ConclusionsEquine OA joints can be distinguished from normal joints based on their FA signatures in SF and its EV-enriched pellet. Clarifying the roles of SF and EV FA compositions in the pathogenesis of OA and their potential as joint disease biomarkers and therapeutic targets warrants future studies.

Mitochondrial Calcium Nanoregulators Reverse the Macrophage Proinflammatory Phenotype Through Restoring Mitochondrial Calcium Homeostasis for the Treatment of Osteoarthritis.

Osteoarthritis (OA) is a chronic degenerative joint disease accompanied by an elevated macrophage proinflammatory phenotype, which is triggered by persistent pathologically elevated calcium ion levels in mitochondria. However, existing pharmacological compounds targeting the inhibition of mitochondrial calcium ion (m[Ca2+]) influx are currently limited in terms of plasma membrane permeability and low specificity for ion channels and transporters. In the present study, we synthesized mesoporous silica nanoparticle-amidated (MSN)-ethylenebis (oxyethylenenitrilo)tetraacetic acid (EGTA)/triphenylphosphine (TPP)-polyethylene glycol (PEG) [METP] nanoparticles (NPs), which specifically target mitochondria and block excess calcium ion influx. m[Ca2+] overload in OA mouse bone marrow-derived macrophages (BMDMs) was detected by a fluorescence probe. A tissue in situ fluorescence colocalization assay was used to evaluate METP NP uptake by macrophages. BMDMs from healthy mice were pretreated with a concentration gradient of METP NPs followed by lipopolysaccharide (LPS) stimulation and detection of m[Ca2+] levels in vitro. The optimal METP NP concentration was further applied, and the endoplasmic reticulum (ER) and cytoplasm calcium levels were detected. The inflammatory phenotype was measured by surface markers, cytokine secretion and intracellular inflammatory gene/protein expression. A Seahorse cell energy metabolism assay was performed to elucidate the mechanism by which METP NPs reverse the BMDM proinflammatory phenotype. The present study identified calcium overload in BMDM mitochondria of OA mice. We demonstrated that METP NPs reversed the increased m[Ca2+] levels in mitochondria and the proinflammatory phenotype of BMDMs, with both in vivo and in vitro experiments, via the inhibition of the mitochondrial aspartate-arginosuccinate shunt and ROS production. We demonstrated that METP NPs are effective and highly specific regulators of m[Ca2+] overload. In addition, we demonstrated that these METP NPs reverse the macrophage proinflammatory phenotype by restoring m[Ca2+] homeostasis, thereby inhibiting the tissue inflammatory response and achieving a therapeutic effect for OA.

CircFNDC3B regulates osteoarthritis and oxidative stress by targeting miR-525-5p/HO-1 axis

Osteoarthritis (OA) is a common chronic degenerative joint disease associated with a variety of risk factors including aging, genetics, obesity, and mechanical disturbance. This study aimed to elucidate the function of a newly discovered circular RNA (circRNA), circFNDC3B, in OA progression and its relationship with the NF-κB signaling pathway and oxidative stress. The circFNDC3B/miR-525-5p/HO-1 axis and its relationship with the NF-κB signaling pathway and oxidative stress were investigated and validated using fluorescence in situ hybridization, real-time PCR, western blotting, immunofluorescence analysis, luciferase reporter assays, pull-down assays, and reactive oxygen species analyses. The functions of circFNDC3B in OA was investigated in vitro and in vivo. These evaluations demonstrated that circFNDC3B promotes chondrocyte proliferation and protects the extracellular matrix (ECM) from degradation. We also revealed that circFNDC3B defends against oxidative stress in OA by regulating the circFNDC3B/miR-525-5p/HO-1 axis and the NF-κB signaling pathway. Further, we found that overexpression of circFNDC3B alleviated OA in a rabbit model. In summary, we identified a new circFNDC3B/miR-525-5p/HO-1 signaling pathway that may act to relieve OA by alleviating oxidative stress and regulating the NF-κB pathway, resulting in the protection of the ECM in human chondrocytes, highlighting it as a potential therapeutic target for the treatment of OA.

Healthy and Osteoarthritis-Affected Joints Facing the Cellular Crosstalk.

Osteoarthritis (OA) is a chronic, progressive, severely debilitating, and multifactorial joint disease that is recognized as the most common type of arthritis. During the last decade, it shows an incremental global rise in prevalence and incidence. The interaction between etiologic factors that mediate joint degradation has been explored in numerous studies. However, the underlying processes that induce OA remain obscure, largely due to the variety and complexity of these mechanisms. During synovial joint dysfunction, the osteochondral unit undergoes cellular phenotypic and functional alterations. At the cellular level, the synovial membrane is influenced by cartilage and subchondral bone cleavage fragments and extracellular matrix (ECM) degradation products from apoptotic and necrotic cells. These "foreign bodies" serve as danger-associated molecular patterns (DAMPs) that trigger innate immunity, eliciting and sustaining low-grade inflammation in the synovium. In this review, we explore the cellular and molecular communication networks established between the major joint compartments-the synovial membrane, cartilage, and subchondral bone of normal and OA-affected joints.