Pathogenesis Of Osteoarthritis Research Articles

Is there a genetic relationship between blood glucose and osteoarthritis? A mendelian randomization study.

The relationship between blood glucose levels and osteoarthritis (OA) is unclear. This study aimed to investigate the genetic causal relationship between blood glucose-related traits and OA. We first performed univariate Mendelian randomization (UVMR) analyses using published genome-wide association study (GWAS) datasets with fasting glucose (FG), 2h-glucose post-challenge glucose (2hGlu), and glycosylated hemoglobin (HbA1c) as exposures, and hip osteoarthritis (HOA) and knee osteoarthritis (KOA) as outcomes; then, we performed inverse analyses of them. We used Inverse-variance weighted (IVW) analysis as the primary analysis, and sensitivity analyses were performed. Moreover, we performed multivariate Mendelian randomization (MVMR) to estimate the independent effect of exposure on outcome after adjusting for body mass index (BMI). Summarized data for blood glucose-related traits were obtained from the MAGIC Consortium study of the glucose trait genome and for OA from the UK Biobank and arcOGEN. Summarized data for BMI were obtained from the GIANT Consortium meta-analysis of individuals of European ancestry. A two-sided p value < 0.05 in UVMR was considered suggestive of significance when p < 0.0167 (Bonferroni correction p = 0.05/3 exposures) was considered statistically significant. We found significant negative genetic causality of FG for HOA and KOA, and these associations remained significant after we adjusted for the effect of BMI [odds ratios (ORs) of 0.829 (0.687-0.999, p = 0.049) and 0.741 (0.570-0.964, p = 0.025)]. HbA1c also had an independent negative genetic causal effect on HOA after adjustment for BMI [0.665 (0.463-0.954, p = 0.027)]. At the same time, there was no evidence of reverse genetic causality of OA on blood glucose-related traits. We further elucidated the relationship between blood glucose-related traits and OA by adjusting for the effect of BMI from a genetic causal perspective. This study provides new insights to further clarify the relationship between blood glucose levels and OA, as well as the pathogenesis, etiology and genetics of OA.

Investigation of GPM6B as a novel therapeutic target in Osteoarthritis.

Osteoarthritis (OA) is the most common motor system disease in older people, characterized by a high incidence and significant social and economic burden. Women have a higher risk of OA, more severe clinical symptoms, and a higher rate of disabilities than men. However, the pathogenesis of OA remains unclear. Therefore, we screened for differentially expressed genes (DEGs) in OA patients of different sex and searched for new targets that may be involved in regulating the development of OA. The study compared the expression of DEGs in synovial fluid exosomes between male and female patients with OA through RNA sequencing combined with bioinformatics analysis using public data. To evaluate the screened DEGs, synovial tissue and fluid samples were obtained from patients with OA who underwent joint replacement surgery. SiRNA-mediated knockdown in vitro experiments were performed to investigate the role of glycoprotein membrane 6B (GPM6B). Meanwhile, GPM6B gene knockout mice were used to assess the in vivo pathological roles of GPM6B in OA. The results revealed that GPM6B is a potential target associated with OA. Immunofluorescence staining demonstrated that GPM6B was expressed in fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes in patients with OA. In vitro experiments confirmed that GPM6B knockdown can reduce the expression of inflammatory factors in primary FLS from patients with OA. Under inflammatory conditions, GPM6B knockdown can reduce the expression of matrix metalloproteinases as well as proliferation of FLS. In addition, using a destabilization of the medial meniscus-induced OA model, we revealed that GPM6B is associated with OA progression in mice. Thus, we provided evidence that GPM6B act as a new target associated with OA.

A PATIENT WITH OSTEOARTHRITIS AND HYPERTENSION IN GENERAL MEDICAL PRACTICE

Osteoarthritis is one of the most common diseases in Ukraine and worldwide, often leading to early disability in people of working age, making it both a medical and social concern. According to the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis, and Musculoskeletal Diseases, as well as the International Society for the Study of Osteoarthritis, it is known that a middle-aged patient with osteoarthritis typically has four accompanying pathologies. In elderly patients, in addition to osteoarthritis, up to eight other chronic conditions are often diagnosed. Comorbidity is frequently observed in middle-aged patients with osteoarthritis. Understanding the pathogenetic links between osteoarthritis and comorbid conditions plays an important role in the timely diagnosis and treatment of these diseases, helping to maintain a high quality of life for patients. Objevtive: the study of the pathogenesis of osteoarthritis and arterial hypertension, along with the proposed therapy for treating comorbidities in patients with both osteoarthritis and arterial hypertension, aims to enhance the treatment outcomes. Materials and methods. Analytical and bibliosemantic methods were used in this study. During the scientific search, 38 modern literature sources were reviewed and analyzed concerning the pathogenetic impact on the development of osteoarthritis and arterial hypertension, as well as their shared mechanisms in the development and progression of both conditions. The study was carried out at the Department of Family Medicine and Therapy of the Regional Rheumatology Center, M. V. Sklifosovsky Poltava Regional Hospital. A total of 50 people were examined; the main group consisted of 35 individuals with stage II hypertension, grade 2, combined with stage II knee osteoarthritis (according to the Kellgren-Lawrence scale), with joint dysfunction of stages 1-2. These patients were aged 40-65 years (mean age 51.8±2.14 years). The duration of hypertension was 10.07±1.24 years, and the duration of manifested osteoarthritis was 8.56±1.03 years. The comparison group consisted of 20 individuals with stage II, grade 2 hypertension (mean age 52.5±2.38 years), with a mean hypertension duration of 11.31±1.17 years. The clinical diagnosis of osteoarthritis was established according to the recommendations of the European Alliance of Associations for Rheumatology (2018). The diagnoses of comorbid conditions were confirmed in accordance with relevant orders from the Ministry of Health of Ukraine, with verification by specialized experts. Patients with osteoarthritis received standard treatment, and, when necessary, additional treatment for comorbid conditions was prescribed (a hypotensive combination of an ACE inhibitor and long-acting calcium. Results: The presence of osteoarthritis exerts an additional negative impact on heart rate variability in patients with hypertension. The reduction of the Low Frequency/High Frequency (LF/HF) index due to the use of this therapy (a combination of an ACE inhibitor and a long-acting calcium antagonist in doses of 4/5 mg, 4/10 mg, 8/5 mg, 8/10 mg) in the treatment of patients with comorbidity of hypertension and osteoarthritis contributes to the activation of the sympathetic nervous system, reduction of patient mortality, balancing of the nervous system by inhibiting sympathetic nervous tone, and lowering high blood pressure. Conclusions: The proposed combination therapy for patients with osteoarthritis and hypertension contributes to prolong remission of both the primary disease and comorbid conditions, reduces the frequency of hospitalizations, and shortens inpatient treatment by 3-4 days.

The role of lncRNA TSIX in osteoarthritis pathogenesis: mechanistic insights and clinical biomarker potential

BackgroundThis study seeks to elucidate the expressions of lncRNA TSIX in Osteoarthritis (OA) and to explore its mechanisms in regulating OA progression.MethodsRT-qPCR was employed to analyze the expression of TSIX in OA patients classified by Kellgren-Lawrence (K-L) grades. Receiver operator characteristic (ROC) was conducted to evaluate the diagnostic value of TSIX. Correlation between TSIX levels and clinical scores such as Lysholm and visual analogue scale (VAS) score was evaluated using Pearson method. IL-1β-induced SW1353 cells served as an in vitro model. The cell function were assessed by flow cytometry and cell counting kit-8 (CCK-8) assay. The relationship between TSIX and miR-320a was verified by luciferase reporting system, while bioinformatics approaches were utilized to predict the downstream target genes of miR-320a.ResultsThe findings revealed that TSIX level in OA patients was elevated compared to that of the control group, with a notable progressive increase in TSIX expression correlated with higher K-L grades. In OA patients, the Lysholm score showed a negative correlation with TSIX expression, while the VAS score displayed a positive correlation with TSIX levels. Cell studies demonstrated that inhibition of TSIX enhanced cell viability and mitigated IL-1β-induced apoptosis by targeting miR-320a, in addition to promoting Aggrecan and Collagen II secretion. Luciferase reporter assay further validated the targeting interaction among TSIX, miR-320a, and PTEN.ConclusionsThis study demonstrated an increased expression of TSIX in OA patients. It suggests that TSIX may play a role in chondrocyte dysfunction during OA by modulating the miR-320a/PTEN axis.

Regulation of ferroptosis in osteoarthritis and osteoarthritic chondrocytes by typical MicroRNAs in chondrocytes

Osteoarthritis (OA) is a progressive degenerative disorder impacting bones and joints, worsened by chronic inflammation, immune dysregulation, mechanical stress, metabolic disturbances, and various other contributing factors. The complex interplay of cartilage damage, loss, and impaired repair mechanisms remains a critical and formidable aspect of OA pathogenesis. At the genetic level, multiple genes have been implicated in the modulation of chondrocyte metabolism, displaying both promotive and inhibitory roles. Recent research has increasingly focused on the influence of non-coding RNAs in the regulation of distinct cell types within bone tissue in OA. In particular, an expanding body of evidence highlights the regulatory roles of microRNAs in OA chondrocytes. This review aims to consolidate the most relevant microRNAs associated with OA chondrocytes, as identified in recent studies, and to elucidate their involvement in chondrocyte metabolic processes and ferroptosis. Furthermore, this study explores the complex regulatory interactions between long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in OA, with an emphasis on microRNA-mediated mechanisms. Finally, critical gaps in the current research are identified, offering strategic insights to advance the understanding of OA pathophysiology and guide therapeutic developments in this field.

Controlled Stimulus-Responsive Delivery Systems for Osteoarthritis Treatment.

Osteoarthritis (OA), a common and disabling degenerative joint disease, affects millions of people worldwide and imposes a considerable burden on patients and society due to its high prevalence and economic costs. The pathogenesis of OA is closely related to the progressive degradation of articular cartilage and the accompany inflammation; however, articular cartilage itself cannot heal and modulate the inflammation due to the lack of nerves, blood vessels, and lymph-vessels. Therefore, reliable and effective methods to treat OA remain highly desired. Local administration of drugs or bioactive materials by intra-articular injection of the delivery system represents a promising approach to treat OA, especially considering the prolonged joint retention, cartilage or chondrocytes targeting, and stimuli-responsive release to achieve precision OA therapy. This article summarizes and discusses the advances in the currently used delivery systems (nanoparticle, hydrogel, liposome, and microsphere) and then focuses on their applications in OA treatment from the perspective of endogenous stimulus (redox reactions, pH, enzymes, and temperature) and exogenous stimulus (near-infrared, magnetic, and ultrasound)-responsive release. Finally, the challenges and potential future directions for the development of nano-delivery systems are summarized.

Increased Rab1a accelerates osteoarthritis by inhibiting autophagy via activation of the mTORC1-S6K pathway

IntroductionCartilage degradation is a critical alteration in the progression of osteoarthritis (OA) due to the disorder of chondrocyte metabolic homeostasis. Autophagy plays an important role in maintaining intracellular homeostasis. Recent investigations have increasingly underscored the importance of autophagy in modulating the pathological mechanisms underlying OA. Ras-related protein Rab-1a (Rab1a) has been illustrated to regulate autophagy in many diseases but not in OA. ObjectivesThis study aims to elucidate whether Rab1a could regulate the development of OA through modulation of chondrocyte autophagy and apoptosis. MethodsProteomic sequencing, Western blotting, and immunohistochemistry were applied to detect the expression level of Rab1a in vitro and in vivo. Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were rigorously identified. The effects of Rab1a and the interaction between Rab1a, mTORC1, autophagy and apoptosis were explored by qPCR, Western blotting, and immunofluorescence. An experimental mouse OA model was also performed to confirm the role of Rab1a in OA pathogenesis in vivo. Histological analysis was employed to demonstrate cartilage damage. ResultsRab1a expression was significantly upregulated in inflamed chondrocytes and knee OA cartilage. Inhibition of Rab1a partially attenuated the degradation of the extracellular matrix and cell apoptosis both in vitro and in vivo, whereas overexpression of Rab1a intensified cartilage matrix degradation and cellular apoptosis. Additionally, elevated Rab1a levels were observed to suppress autophagy and activate the mTORC1-S6K signaling pathway, thereby aggravating OA pathogenesis. ConclusionThe augmentation of Rab1a expression impairs autophagy and promotes apoptosis through the activation of the mTORC1-S6K signaling pathway, further exacerbating OA pathogenesis. This finding suggests that Rab1a serves as a promising and innovative therapeutic target for the prevention and treatment of OA.

Matrikine stimulation of equine synovial fibroblasts and chondrocytes results in an in vitro osteoarthritis phenotype.

Osteoarthritis (OA) is a debilitating disease that impacts millions of individuals and has limited therapeutic options. A significant hindrance to therapeutic discovery is the lack of in vitro OA models that translate reliably to in vivo preclinical animal models. An alternative to traditional inflammatory cytokine models is the matrikine stimulation model, in which fragments of matrix proteins naturally found in OA tissues and synovial fluid, are used to stimulate cells of the joint. The objective of this study was to determine if matrikine stimulation of equine synovial fibroblasts and chondrocytes with fibronectin fragments (FN7-10) would result in an OA phenotype. We hypothesized that FN7-10 stimulation of equine articular cells would result in an OA phenotype with gene and protein expression changes similar to those previously described for human chondrocytes stimulated with FN7-10. Synovial fibroblasts and chondrocytes isolated from four horses were stimulated in monolayer culture for 6 or 18 h with 1 µM purified recombinant 42 kD FN7-10 in serum-free media. At the conclusion of stimulation, RNA was collected for targeted gene expression analysis and media for targeted protein production analysis. Consistent with our hypothesis, FN7-10 stimulation resulted in significant alterations to many important genes that are involved in OA pathogenesis including increased expression of IL-1β, IL-4, IL-6, CCL2/MCP-1, CCL5/RANTES, CXCL6/GCP-2, MMP-1, MMP-3, and MMP13. The results of this study suggest that the equine matrikine stimulation model of OA may prove useful for in vitro experiments leading up to preclinical trials.

Why is therapeutic exercise the best treatment for knee osteoarthritis?

Osteoarthritis (OA) of the knee joints (KJ) has a high social significance and is therefore a relevant pathology for scientific research. The authors have proposed an original hydraulic theory for the pathogenesis of OA in KJ. This approach is based on the notion of primary mechanical damage to the internal ligamentous structures and synovial membrane accompanied by posttraumatic edema, synovial hypervolemia, and hypertension. The authors demonstrated that regular physical activity at all stages of the disease is pathogenetically justified and allows the patient to improve lymphatic and venous outflow and thus resist increasing fibrosis. Improved arterial blood flow will reduce tissue hypoxia. Any type of symptom-modifying therapy can be harmful because it reduces the protective role of pain reflexes in protecting the KJ from excessive loads, leading to injury. The necessity of maintaining a walking speed of more than 4.3 km/h with an increase in cadence is emphasized from the perspective of reducing static stress during walking and extending life expectancy.

Analyzing the Role of Specific Damage-Associated Molecular Patterns-Related Genes in Osteoarthritis and Investigating the Association between β-Amyloid and Apolipoprotein E Isoforms.

Osteoarthritis (OA) is a prevalent chronic joint disorder. It is characterized by an immune response that maintains a low level of inflammation throughout its progression. During OA, cartilage degradation leads to the release of damage-associated molecular patterns (DAMPs), which intensify the inflammatory response. β-Amyloid is a well-recognized DAMP in OA, can interact with APOE isoforms. This study identified DAMPs-related genes in OA using bioinformatics techniques. Additionally, we examined the expression levels of β-amyloid and apolipoprotein E (ApoE) isoforms by enzyme-linked immunosorbent assay. We identified 10 key genes by machine learning techniques. Immune infiltration analysis revealed upregulation of various immune cell types in OA cartilage, underscoring the critical role of inflammation in OA pathogenesis. In the validation study, elevated serum levels of β-amyloid in knee osteoarthritis (KOA) patients were confirmed, showing positive correlations with ApoE2 and ApoE4. Notably, ApoE3 was identified as an independent protective factor against KOA. In this bioinformatics analysis, we identified the DAMPs-related genes of KOA and explored their potential functions and regulatory networks. The high expression of β-amyloid in KOA was confirmed by experiments, and the correlation between β-amyloid and ApoE2, ApoE4 in KOA was revealed for the first time, this provides a new way to explore the pathogenesis of KOA and to study the therapeutic targets of KOA.

IRF1-mediated upregulation of PARP12 promotes cartilage degradation by inhibiting PINK1/Parkin dependent mitophagy through ISG15 attenuating ubiquitylation and SUMOylation of MFN1/2

Osteoarthritis (OA) is an age-related cartilage-degenerating joint disease. Mitochondrial dysfunction has been reported to promote the development of OA. Poly (ADP-ribose) polymerase family member 12 (PARP12) is a key regulator of mitochondrial function, protein translation, and inflammation. However, the role of PARP12 in OA-based cartilage degradation and the underlying mechanisms are relatively unknown. Here, we first demonstrated that PARP12 inhibits mitophagy and promotes OA progression in human OA cartilage and a monosodium iodoacetate-induced rat OA model. Using mass spectrometry and co-immunoprecipitation assay, PARP12 was shown to interact with ISG15, upregulate mitofusin 1 and 2 (MFN1/2) ISGylation, which downregulated MFN1/2 ubiquitination and SUMOylation, thereby inhibiting PINK1/Parkin-dependent chondrocyte mitophagy and promoting cartilage degradation. Moreover, inflammatory cytokine-induced interferon regulatory factor 1 (IRF1) activation was required for the upregulation of PARP12 expression, and it directly bound to the PARP12 promoter to activate transcription. XAV-939 inhibited PARP12 expression and suppressed OA pathogenesis in vitro and in vivo. Clinically, PARP12 can be used to predict the severity of OA; thus, it represents a new target for the study of mitophagy and OA progression. In brief, the IRF1-mediated upregulation of PARP12 promoted cartilage degradation by inhibiting PINK1/Parkin-dependent mitophagy via ISG15-based attenuation of MFN1/2 ubiquitylation and SUMOylation. Our data provide new insights into the molecular mechanisms underlying PARP12-based regulation of mitophagy and can facilitate the development of therapeutic strategies for the treatment of OA.

Bioactive Compounds and Their Chondroprotective Effects for Osteoarthritis Amelioration: A Focus on Nanotherapeutic Strategies, Epigenetic Modifications, and Gut Microbiota.

In degenerative joint disease like osteoarthritis (OA), bioactive compounds like resveratrol, epigallocatechin gallate, curcumin, and other polyphenols often target various signalling pathways, including NFκB, TGFβ, and Wnt/β-catenin by executing epigenetic-modifying activities. Epigenetic modulation can target genes of disease pathophysiology via histone modification, promoter DNA methylation, and non-coding RNA expression, some of which are directly involved in OA but have been less explored. OA patients often seek options that can improve the quality of their life in addition to existing treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). Although bioactive and natural compounds exhibit therapeutic potential against OA, several disadvantages loom, like insolubility and poor bioavailability. Nanoformulated bioactive compounds promise a better way to alleviate OA since they also control systemic events, including metabolic, immunological, and inflammatory responses, by modulating host gut microbiota that can regulate OA pathogenesis. Recent data suggest gut dysbiosis in OA. However, limited evidence is available on the role of bioactive compounds as epigenetic and gut modulators in ameliorating OA. Moreover, it is not known whether the effects of polyphenolic bioactive compounds on gut microbial response are mediated by epigenetic modulatory activities in OA. This narrative review highlights the nanotherapeutic strategies utilizing bioactive compounds, reporting their effects on chondrocyte growth, metabolism, and epigenetic modifications in osteoarthritis amelioration.

RNA sequencing uncovers key players of cartilage calcification: potential implications for osteoarthritis pathogenesis.

Osteoarthritis (OA) is a joint disease linked with pathologic cartilage calcification, caused by the deposition of calcium-containing crystals by chondrocytes. Despite its clinical significance, the precise mechanisms driving calcification remain elusive. This study aimed to identify crucial players in cartilage calcification, offering insights for future targeted interventions against OA. Primary murine chondrocytes were stimulated with secondary calciprotein particles (CPP2) or left untreated (NT) for 6 h. Calcification was assessed by alizarin red staining. RNA was analyzed by Bulk RNA sequencing. Differentially expressed (DE) genes were identified (cutoff: abs(LogFC)>1 and adj.p-val < 0.05), and top 50 DE genes were cross-referenced with human OA datasets from previous studies (ie healthy vs OA cartilage, or undamaged vs damaged cartilage). RNA from NT and CPP2-stimulated primary human OA chondrocytes were used to validate genes by qPCR. CPP2 induced crystal formation by chondrocytes and significantly modulated 1466 genes. Out of the top 50 DE genes in CPP2, 27 were confirmed in published OA cartilage datasets. Of those genes, some are described in calcification and/or OA (Errfi1, Ngf, Inhba, Col9a1). Two additional ones (Rcan1, Tnfrsf12a) appear novel and interesting in the context of calcification and OA. We validated modulation of these six genes in calcifying human chondrocytes from 5 patients. Ultimately, we unveiled two distinct gene families modulated by CPP2: the first comprised cytoskeletal genes (Actb, Tpm1, Cfl1, Tagln2, Lmna), while the second encompassed extracellular matrix genes (Fmod, Sparc, Col9a1, Cnmd). CPP2 modulates genes in chondrocytes that could represent new targets for therapeutic interventions in OA.

Senolytic therapy combining Dasatinib and Quercetin restores the chondrogenic phenotype of human osteoarthritic chondrocytes by the release of pro-anabolic mediators.

Cellular senescence is associated with various age-related disorders and is assumed to play a major role in the pathogenesis of osteoarthritis (OA). Based on this, we tested a senolytic combination therapy using Dasatinib (D) and Quercetin (Q) on aged isolated human articular chondrocytes (hACs), as well as in OA-affected cartilage tissue (OARSI grade 1-2). Stimulation with D + Q selectively eliminated senescent cells in both, cartilage explants and isolated hAC. Furthermore, the therapy significantly promoted chondroanabolism, as demonstrated by increased gene expression levels of COL2A1, ACAN, and SOX9, as well as elevated collagen type II and glycosaminoglycan biosynthesis. Additionally, D + Q treatment significantly reduced the release of SASP factors (IL6, CXCL1). RNA sequencing analysis revealed an upregulation of the anabolic factors, inter alia, FGF18, IGF1, and TGFB2, as well as inhibitory effects on cytokines and the YAP-1 signaling pathway, explaining the underlying mechanism of the chondroanabolic promotion upon senolytic treatment. Accordingly, stimulation of untreated hAC with conditioned medium of D + Q-treated cells similarly induced the expression of chondrogenic markers. Detailed analyses demonstrated that chondroanabolic effects could be mainly attributed to Dasatinib, while monotherapeutical application of Quercetin or Navitoclax did not promote the chondroanabolism. Overall, D + Q therapy restored the chondrogenic phenotype in OA hAC most likely by creating a pro-chondroanabolic environment through the reduction of SASP factors and upregulation of growth factors. This senolytic approach could therefore be a promising candidate for further testing as a disease-modifying osteoarthritis drug.

Wedelolactone alleviates inflammation and cartilage degeneration by suppressing the NF-κB signaling pathway in osteoarthritis

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.

The Role of Adipokines between Genders in the Pathogenesis of Osteoarthritis

Osteoarthritis (OA) is a chronic, progressive, degenerative joint disease characterized by joint pain, stiffness, and limited movement. It presents significant intra- and inter-individual variability—in particular, between genders. Recent research has increasingly focused on the role of adipokines—especially leptin, adiponectin, and resistin—in the development of OA. Adipokines, peptide hormones primarily secreted by adipose tissue, are involved in crucial physiological processes related to metabolism and immunity. They can also impact bone and cartilage turnover by interacting with joint cells such as osteoblasts, osteoclasts, chondrocytes, and mesenchymal stem cells, thereby linking inflammation with bone cartilage homeostasis. This review aims to elucidate the structure and functions of various adipokines, their serum and synovial levels, and their association with clinical presentation and radiographic progression in OA patients, with a focus on differences between sexes. A narrative literature review was conducted using three databases specifically analyzing sex differences. OA patients generally show elevated serum and synovial levels of leptin, chemerin, and visfatin, as well as high plasma levels of resistin and visfatin. In contrast, synovial levels of adiponectin and omentin are reduced in OA patients compared to healthy individuals, with an inverse relationship to disease severity, suggesting a potential protective role. Resistin and leptin were positively correlated with pain severity and radiographic progression, while adiponectin’s role in OA remains controversial. Regarding sex differences, male OA patients exhibited higher serum levels of leptin, chemerin, and omentin compared to healthy controls, with a positive correlation to the BMI and estrogen levels, potentially explaining the sexual dimorphism observed in this condition. Studies on visfatin and lipocalin did not reveal significant differences in synovial or serum levels between the sexes. The role of resistin remains controversial. Adipokines influence the joint microenvironment and contribute to the progression of osteoarthritis (OA). However, the precise biological mechanisms are not yet fully understood due to the complex interactions between the metabolic, mechanical, and immune systems. Further research is needed to clarify their roles in OA and to identify targeted therapies for managing this degenerative disease.

Bibliometric analysis of chondrocyte apoptosis in knee osteoarthritis.

Apoptosis, a form of programmed cell death, plays a significant role in osteoarthritis; however, bibliometric studies in this field remain scarce. Bibliometrics provides a visual representation of research outcomes and trends, guiding future investigations. Journal data from January 1, 2013, to December 31, 2023, in this field were obtained from the Web of Science (WOS) core database. Analysis was conducted using VOSviewer and CiteSpace. Analysis revealed that over the past decade, 794 articles were published in 299 journals by 4447 authors from 49 countries and 877 institutions. The top contributors were China, the United States, and the United Kingdom. Zhuang Chao emerged as the most prolific author, and "osteoarthritis and cartilage" ranked as the most frequently cited journal. Keyword clustering focused on mechanisms, inflammation, and cartilage. The most-cited article was "chondrocyte apoptosis in the pathogenesis of osteoarthritis" in the "International Journal of Molecular Sciences." Burst word analysis highlighted extracellular matrix, circular RNA, micro RNA, indicating current research hotspots. Utilizing bibliometrics and visual analysis, we explored the hotspots and trends in the field of chondrocyte apoptosis in osteoarthritis. Extracellular matrix, Circular RNA, Micro RNA, among others, are likely to become future research focal points and frontiers.

The Mechanism by Which Cyperus rotundus Ameliorates Osteoarthritis: A Work Based on Network Pharmacology.

Cyperus rotundus (CR) is widely used in traditional Chinese medicine to prevent and treat a variety of diseases. However, its functions and mechanism of action in osteoarthritis (OA) has not been elucidated. Here, a comprehensive strategy combining network pharmacology, molecular docking, molecular dynamics simulation and in vitro experiments was used to address this issue. The bioactive ingredients of CR were screened in TCMSP database, and the potential targets of these ingredients were obtained through Swiss Target Prediction database. Genes in OA pathogenesis were collected through GeneCards, OMIM and DisGeNET databases. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed using DAVID database. STRING database and Cytoscape 3.10 software were used to construct "component-target-pathway" network, and predict the core targets affected by CR. The binding affinity between bioactive components and the core targets was evaluated by molecular docking and molecular dynamics simulation. The therapeutic activity of kaempferol on chondrocytes in inflammatory conditions was verified by in vitro experiments. Fifteen CR bioactive ingredients were obtained, targeting 192 OA-related genes. A series of biological processes, cell components, molecular functions and pathways were predicted to be modulated by CR components. The core targets of CR in OA treatment were AKT serine/threonine kinase 1 (AKT1), interleukin 1 beta (IL1B), SRC proto-oncogene, non-receptor tyrosine kinase (SRC), BCL2 apoptosis regulator (BCL2), signal transducer and activator of transcription 3 (STAT3), epidermal growth factor receptor (EGFR), hypoxia-inducible factor 1 subunit alpha (HIF1A), matrix metallopeptidase 9 (MMP9), estrogen receptor 1 (ESR1) and PPARG orthologs from vertebrates (PPARG), and the main bioactive ingredients of CR showed good binding affinity with these targets. In addition, kaempferol, one of the CR bioactive components, weakens the effects of IL-1β on the viability, apoptosis and inflammation of chondrocytes. Theoretically, CR has great potential to ameliorate the symptoms and progression of OA, via multiple components, multiple targets, and multiple downstream pathways.

Carbonic anhydrase 2 is important for chondrocyte function and metabolic homeostasis

ObjectivesAberrant chondrocyte metabolism significantly contributes to cartilage degeneration and osteoarthritis (OA) genesis. However, the mechanisms driving the metabolic shift in OA chondrocytes remain unclear. Interestingly, carbonic anhydrase 2 (CA2) is implicated in metabolic regulation, and its expression dramatically increases in OA chondrocytes, but its exact role and mechanism are poorly understood. This study investigates the mechanistic role of CA2 in chondrocyte metabolic homeostasis under inflammatory conditions. MethodsRNA-seq was performed on CA2-deficient C28/I2 cells to identify pathways affected by the loss of CA2 function. We examined CA2's impact on chondrocyte metabolism, anabolism, and catabolism using C28/I2 cells and primary chondrocytes under normoxia and hypoxia and in a model of inflammatory OA. ResultsRNA-seq revealed enrichment of glycolysis, apoptosis, and TNF signaling pathways in CA2-deficient cells. Under hypoxia, CA2 expression increased 10-fold in a HIF-1α-independent manner. Knockdown of CA2 reduced extracellular lactate production, increased ADP/ATP ratio, impaired glycolysis, reduced glycolytic capacity, and lowered expression of glycolysis rate-limiting enzymes but did not disrupt pHi and ROS production. CA2 deficiency altered chondrocyte anabolic and catabolic equilibrium by affecting PI3K/AKT and RELA/p65 signaling. Chondrocyte migration was impeded, proliferation suppressed, and the cell cycle arrested at G0/G1 in cells lacking CA2. Forced expression of CA2 stabilized chondrocyte metabolism and restored cellular functions. ConclusionsOur research uncovered a novel mechanistic role for CA2 in regulating chondrocyte energy metabolism and inflammation, underscoring its potential as a critical mediator in OA pathogenesis. Further research using a murine model of experimental OA is warranted to capture the functional implications of CA2.

Alterations in Immune Parameters ADP, ANA, IL-1, IL-6, IL-8, STAT-4, and TNF Alpha in Patients with Rheumatoid Arthritis and Osteoarthritis

Background: Rheumatoid arthritis (RA) and osteoarthritis (OA) are chronic joint diseases with distinct pathophysiological mechanisms, but both involve alterations in immune parameters. This research investigates the alterations in several immune parameters, specifically adiponectin (ADP), antinuclear antibodies (ANA), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), signal transducer and activator of transcription 4 (STAT-4), and tumor necrosis factor-alpha (TNF Alpha), in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Also, the current study aims to identify the changes occurring in the physiological and immune parameters of people suffering from rheumatic diseases, as Evaluation of Immunological Inflammatory biomarkers levels ADP, ANA, IL1, IL6, IL8, STAT-4 and TNF-α. Material &amp; Methods: A cross-sectional laboratory-based study with 90 patient’s participant was conducted. Using ELISA kits and laboratory tests, various biomarkers (Immunological Inflammatory biomarkers levels ADP, ANA, IL1, IL6, IL8, STAT-4 and TNF-α were measured among rheumatoid arthritis and Osteoarthritis patients. Results: The findings revealed elevated levels of IL-1, IL-6, IL-8, STAT-4, and TNF Alpha in RA patients, reflecting a heightened inflammatory state. In contrast, OA patients exhibited a more moderate increase in these parameters, suggesting differing immune activation pathways. ADP and ANA levels showed distinct variations between the two patient groups, indicating their potential roles in the pathogenesis and progression of RA and OA. Conclusion: These results contribute to a better understanding of the immune mechanisms underlying RA and OA, highlighting the importance of targeted therapeutic strategies to manage these conditions effectively. Further research is recommended to explore the clinical implications of these findings and develop personalized treatment approaches.