Intra-articular targeted delivery of nanomaterials for the treatment of osteoarthritis: focusing on cell signaling pathway mechanisms

The role of primary cilia in cartilage health and disease

Antioxidant, antiinflammatory and neuroprotective actions of chondroitin sulfate and proteoglycans

Clinical review of chondroitin sulfate in osteoarthritis

Osteoarthritis (OA) is the most common joint disease, which mainly damages articular cartilage and involves the whole joint tissue. It has the characteristics of long course, repeated symptoms and high disability rate, and the incidence trend is gradually increasing. Tetramethylpyrazine (TMP) is the main alkaloid active substance in Ligusticum wallichii, a traditional Chinese medicine, which has the effect of promoting blood circulation and dredging collaterals, and has a good effect on the treatment of early OA, but its molecular mechanism has not been fully clarified so far. Based on network pharmacology, molecular docking simulation and animal experiments, this study explored the target and molecular mechanism of TMP in the treatment of OA. We used PubChem, SwissTargetPrediction, and PharmMapper databases to predict the molecular structure and potential targets of TMP. GeneCards and DisGeNET databases were used to predict the relevant targets of OA. Apply UniProt database to convert targets into unified gene names, and proofread and remove duplicate gene names. The intersection targets of TMP and OA obtained on venny2.1.0 website were submitted to the STRING database to construct a PPI network. CytoScape 3.8.2 software was used to analyze the PPI network and obtain the sub-network modules and 10 key targets. The intersection targets of TMP and OA were analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment using DAVID 6.8 database. The intersecting targets of TMP and OA, the biological process of GO enrichment, and KEGG signaling pathway were imported into Cytoscape 3.8.2 software to construct the TMP-target-pathway network diagram. Use molecular docking technology to simulate the interaction between TMP molecules and key targets, and predict the binding mode and binding ability. Animal models of rabbit knee osteoarthritis were prepared, and magnetic resonance imager (MRI) and fluorescence quantitative PCR (RT-qPCR) were used to observe the effect of TMP in treating OA as well as the expression of key target genes. 585 potential targets of TMP, 3,857 potential targets of OA, and 49 intersecting targets of TMP and OA were obtained. The top 10 key target genes were obtained, in order of ranking: ALB, ESR1, IL10, CAT, F2, MPO, C3, CYP3A4, CYP2C9, ANXA1. GO and KEGG analysis implied that the key targets might act on OA by affecting endothelial cell permeability, peri-articular microcirculatory status, NETs production, activation of complement system and coagulation pathway, regulation of immune function of macrophages and T cells, and substance metabolism pathway in vivo, etc. The molecular mechanism might involve the formation of neutrophil extracellular trap, regulation of the actin cytoskeleton, complement and coagulation cascades, and T cell receptor signaling pathways, etc. Molecular docking simulations showed that the binding energy of IL10 and ANXA1 to TMP was greater than -5Kal/mol, but the other key target proteins showed better binding to TMP, and the binding energy was less than -5kcal/mol. Animal experiments showed that TMP had a significant therapeutic effect on OA. The TMP group had significantly reduced knee joint effusion and bone marrow damage compared to the OA group (p < 0.05). The qRT-PCR results showed that compared with the OA group, the mRNA expression of ESR1, CAT, C3, CYP3A4, CYP2C9, and ANXA1 in the TMP group increased (p < 0.05), while there was no significant difference in mRNA expression of ALB, IL-10, F2, MPO, etc. (p > 0.05). TMP is effective in the treatment of OA, with multi-target and multi-pathway interactions. ESR1, CAT, C3, CYP3A4, CYP2C9, and ANXA1 may be potential targets for TMP treatment of OA. The molecular mechanism mainly involves the formation of neutrophil extracellular trap, regulation of the actin cytoskeleton, complement and coagulation cascades, and T cell receptor signaling pathways, etc.

Decipher the action mechanism of Simiao Pill in the treatment of knee osteoarthritis by integrating network pharmacology

Clinical experience indicates that aquatic exercise may have advantages for osteoarthritis patients. To compare the effectiveness and safety of aquatic-exercise interventions in the treatment of knee and hip osteoarthritis. We searched MEDLINE from 1949, EMBASE from 1980, CENTRAL (Issue 2, 2006), CINAHL from 1982, Web of Science from 1945, all up to May 2006. There was no language restriction. Randomised controlled trials or quasi-randomised clinical trials. Two review authors independently selected trials for inclusion, assessed the internal validity of included trials and extracted data. Pooled results were analyzed using standardized mean differences (SMD). There is a lack of high-quality studies in this area. In total, six trials (800 participants) were included. At the end of treatment for combined knee and hip osteoarthritis, there was a small-to-moderate effect on function (SMD 0.26, 95% confidence interval (CI) 0.11 to 0.42) and a small-to-moderate effect on quality of life (SMD 0.32, 95% CI 0.03 to 0.61). A minor effect of a 3% absolute reduction (0.6 fewer points on a 0 to 20 scale) and 6.6% relative reduction from baseline was found for pain. There was no evidence of effect on walking ability or stiffness immediately after end of treatment. No evidence of effect on pain, function or quality of life were observed on the one trial including participants with hip osteoarthritis alone. Only one trial was identified including knee osteoarthritis alone, comparing aquatic exercise with land-based exercise. Immediately after treatment, there was a large effect on pain (SMD 0.86, 95%CI 0.25 to 1.47; 22% relative percent improvement), but no evidence of effect on stiffness or walking ability. Only two studies reported adverse effects, that is, the interventions did not increase self-reported pain or symptom scores. No radiographic evaluation was performed in any of the included studies. Aquatic exercise appears to have some beneficial short-term effects for patients with hip and/or knee OA while no long-term effects have been documented. Based on this, one may consider using aquatic exercise as the first part of a longer exercise programme for osteoarthritis patients. The controlled and randomised studies in this area are still too few to give further recommendations on how to apply the therapy, and studies of clearly defined patient groups with long-term outcomes are needed to decide on the further use of this therapy in the treatment of osteoarthritis.

This study was conducted to identify whether the TLR4/MyD88/NF-κB signalling pathway plays a vital role in osteoarthritis (OA) treatment with Duhuo Jisheng Decoction (DHJSD) on the basis of a network pharmacology approach (NPA)-integrated experiment. Two experiments were conducted as follow: NPA for DHJSD using six OA-related gene series and the key pathway was screened out using NPA. NPA identified a vital role for the TLR4/MyD88/NF-κB signalling pathway in OA treatment with DHJSD, the conventional western blot analysis and qPCR confirmed it. Furthermore, changes of miR-146a-5p and miR-34a-5p in the cellular models were recovered by DHJSD administration, which synergistically contributed to OA therapy. The toll-like receptor signalling pathway and the NF-κB signalling pathway were meaningfully enriched by the miRNA-regulated gene pathways. This study identified and confirmed the TLR4/MyD88/NF-κB signalling pathway is an essential inflammatory signalling pathway in the DHJSD underlying OA treatment. The results provide a basis for further evaluation of the regulatory mechanism of the drug’s efficacy in treating OA.

Osteoarthritis (OA) as the most frequent form of knee arthritis is one of the most annoying complications amongst old peoples. There are different pharmacological and non-pharmacological remedies which could be applied for treatment of knee OA. It's while, significant side effects mostly in patients who are older are the dangerous limiting factors. Integrative, supplementary, traditional remedies have been applied from long time ago in treatment of such chronic diseases like OA. Various topical and oral remedies have been presented in treatment of OA worldwide. In spite of the fact there are multiple remedies for reduction symptoms of patients who suffer from disorders and related inabilities which could enhance their life quality. Remedies which have been applied for a long time for treatment of OA have newly discovered to induce injury to some patients. On the other side, additional knowledge about alternative and supplementary remedies is a main way for enhancing health of patients who suffer from OA disorders. Zingiber zerumbet (Z. zerumbeton) is a kind of herb of the ginger family and is a natural compound with various biomedical characteristics like anti-proliferative, anti-inflammatory, and antioxidant effect. However, Z. zerumbet could be applied for reduction of OA symptoms because of its circulatory stimulant and anti-inflammatory effects. Anyway, up to now there is not any methodical literature review for evaluating the Z. zerumbet clinical effectiveness productiveness in treatment of OA. The main aim of the current study is to review scientific resources around therapeutic effectiveness of Zingiber zerumbet in treatment of adverse symptoms of OA disorder.

Osteoarthritis(OA) is a kind of osteoarticular degenerative disease. The most common joint involvement of OA is knee and hip joint. The incidence rate of OA increases with age. Meta analysis shows that moxibustion is superior to other therapies in treating knee osteoarthritis(KOA). In this study, the effects of moxibustion materials from different places of origin(Hubei Qichun, Henan Nanyang, Hunan) and storage periods(5, 3, 1 years) on knee osteoarthritis in rats were compared. The swelling degree of knee joint and the histopathology of knee joint cartilage were measured. The mechanism of moxibustion in the treatment of knee osteoarthritis was discussed from the perspective of Wnt/β-catenin signaling pathway. The results showed that the swelling degree of knee joint in the moxibustion material group of Hubei Qichun and Henan Nanyang was significantly lower than that in the model group, the diffe-rence was statistically significant(P&lt;0.05), and it was better than that in the moxibustion material group of Hunan Province; compared with the model group, the degeneration and pathological change of knee joint cartilage tissue in the moxibustion material group of different origins were alleviated to different degrees, the Mankin's score was significantly reduced, and that in the moxibustion material group of Qichun in Hubei Province and Nanyang in Henan Province was significantly reduced and better than Hunan moxibustion material group. The effect of moxibustion materials with different storage years on the swelling degree of osteoarthritis in rats was the earliest in Qichun 5-year group, and there was significant difference between Qichun 5-year group and model group after 3 days of treatment; the improvement of histopathological changes in Qichun 5-year and 3-year moxibustion materials group was better than that in Qichun 1-year moxibustion materials group. The study on the mechanism of action showed that moxibustion materials from different places could reduce the mRNA expression of β-catenin, BMP-2, MMP-3, MMP-9 and MMP-13 genes in knee cartilage, suggesting that moxibustion could inhibit cartilage base by regulating Wnt/β-catenin signal pathway. It may be one of the mechanisms of moxibustion in the treatment of OA.

Background:Osteoarthritis (OA) is the leading cause of disability in the elderly. Prevention and treatment of OA have become an urgent global demand. The pharmacologic role of diacerein in the treatment of osteoarthritis is controversial. We systematically reviewed the efficacy, safety, and residual effectiveness of diacerein.Objectives:To estimate the symptomatic efficacy, residual effect and safety of diacerein in the treatment of knee osteoarthritis, using a meta-analysis of published randomized controlled trials (RCTs).Methods:On December 1, 2021, we searched PubMed Medline, Web of Science, Cochrane Library databases, Wan Fang Medical Database, and National Knowledge Infrastructure. This study followed the inclusion criteria of the principle P(Population), I(Intervention), C(Comparison), O(Outcome), S (Study design) principle. All studies were randomized controlled trials of knee osteoarthritis. Cochrane bias risk assessment tool was used to assess the risk of bias. Meta-analyses were performed using a random-effects model. To explore sources of heterogeneity, subgroup analysis, sensitivity analysis, regression analysis and publication bias analysis were performed. Drug side effects with complete data were extracted from the included articles and then a combined analysis of these data was performed.Results:Eight studies were eligible and were included in our analysis (N = 1277 participants). All studies were randomized controlled trials of knee osteoarthritis. There was no significant difference in reduction of joint pain and improvement of function between diacerein and the control group. However, subgroup analysis suggested, compared with the placebo group, diacerein treatment yielded an improved mean reduction in visual analogue scale score of-0.44% (95% confidence interval [CI]-0.79 to 0.09), an improved the western Ontario and McMaster universities (physical function) score of -0.44% (95% CI-0.72 to -0.12). Follow-up analysis after discontinuation showed that diacerein treatment had a significant residual effect (95% CI-0.81 to- 0.24). Data on drug side effects described in the included articles were extracted for statistical analysis. There was an increased risk of diarrhea with diacerein (Risk Ratio [RR] = 1.95 [1.03 to 2.47]) and withdrawal event from therapy (RR = 0.93 [0.75 to 1.15]).Conclusion:Diacerein might be considered an effective drug for the treatment of patients with KOA, showing short-term residual effectiveness. Although it is associated with an increased risk of diarrhea, the adverse event is mostly tolerable.

Objective This study aimed to explore the mechanism of Modified Danggui Sini Decoction in the treatment of knee osteoarthritis via a combination of network pharmacology and molecular docking. Methods The main chemical components and corresponding targets of Modified Danggui Sini Decoction were searched and screened in TCMSP database. The disease targets of knee osteoarthritis were summarized in GeneCards, OMIM, PharmGkb, TTD, and DrugBank databases. The visual interactive network of “drugs-active components-disease targets” was drawn by Cytoscape 3.8.1 software. The protein-protein interaction network was constructed by STRING database. Then, GO function and KEGG pathway enrichment were analyzed by Bioconductor/R, and the pathway of the highest degree of correlation with knee osteoarthritis was selected for specific analysis. Finally, molecular docking was used to screen and verify core genes by AutoDockTools software. Results Seventy-one main components of Modified Danggui Sini Decoction and 116 potential therapeutic targets of knee osteoarthritis were selected. The KEGG pathway and the GO function enrichment analysis showed that the targets of Modified Danggui Sini Decoction in the treatment of knee osteoarthritis were mainly concentrated on PI3K-Akt signaling pathway, TNF signaling pathway, IL-17 signaling pathway, apoptosis signaling pathway, Toll-like receptor signaling pathway, Th17 cell differentiation signaling pathway, HIF-1 signaling pathway, and NF-κB signaling pathway. It mainly involved inflammatory reaction, regulation of apoptotic signaling pathway, cellular response to regulation of inflammatory response, cellular response to oxidative stress, and other biological processes. The molecular docking results showed that ESR1-wogonin, MAPK1-quercetin, RELA-wogonin, RELA-baicalein, TP53-baicalein, TP53-quercetin, and RELA-quercetin have strong docking activities. Conclusion Modified Danggui Sini Decoction has the hierarchical network characteristics of “multicomponent, multitarget, multifunction, and multipathway” in the treatment of knee osteoarthritis. It mainly regulates the proliferation and apoptosis of chondrocytes by regulating the PI3K-Akt signaling pathway and establishes cross-talk with many downstream inflammatory-related pathways to reduce the overall inflammatory response. Meanwhile, HIF-1 expression was used to ensure the normal function and metabolism of knee joint under hypoxia condition, and the above processes play a key role in the treatment of knee osteoarthritis.

http://rehabilitation.cochrane.org The aim of this commentary is to discuss in a rehabilitation perspective the published Cochrane Review “Paracetamol vs placebo for knee and hip osteoarthritis1” by Leopoldino et al.,a under the direct supervision of the Cochrane Musculoskeletal Group. This Cochrane Corner is produced in agreement with the International Journal of Rheumatic Disease by Cochrane Rehabilitation. Osteoarthritis is a widespread disease, and one of the most common causes of pain, stiffness, reduced quality of life and, ultimately, disability.2 The cornerstone of any intervention on knee and hip osteoarthritis is pain relief.3 Paracetamol is widely perceived as a safe drug, especially compared to other analgesics such as non-steroidal anti-inflammatory drugs. Currently, many guidelines propose paracetamol as first-line analgesic for hip and knee osteoarthritis.4, 5 However, paracetamol is not free from risks, as it has been linked with increased risk of gastrointestinal, cardiovascular, and kidney diseases, and mortality.6 Moreover, studies have reported that paracetamol has only a small effect on hip and knee osteoarthritis, compared to placebo.7 A Cochrane review addressed this issue investigating current evidence on the efficacy of paracetamol vs placebo in knee and hip osteoarthritis.1 (Leopoldino AO, Machado GC, Ferreira PH, Pinheiro MB, Day R, McLachlan AJ, Hunter DJ, Ferreira ML, 2019) The aim of this Cochrane review was to assess benefits and harms of paracetamol for the treatment of knee and hip osteoarthritis compared with use of placebo. The population addressed in this review included adult patients with osteoarthritis of the hip or knee of any level of health care. The interventions studied were randomized controlled trials comparing benefits and harm of only paracetamol administration vs placebo for the treatment of hip or knee osteoarthritis. The major outcomes were pain intensity, physical function, quality of life, adverse events, withdrawals due to adverse events and liver toxicity. The review authors searched for studies that had been published up to October 2017 in the Cochrane Register of Controlled Trials, MEDLINE, Embase, AMED, CINAHL, Web of Science, LILACS, International Pharmaceutical Abstracts, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (ICTRP). The review included 10 randomized placebo-controlled trials enrolling a total of 3541 adult patients with knee or hip osteoarthritis. The authors concluded there is high-quality evidence that paracetamol can only minimally affect pain and physical function in people suffering from knee or hip osteoarthritis in the immediate and short term regardless of the dosage, with no risk of adverse events. Moreover, moderate-quality evidence shows that paracetamol increases the number of abnormal liver function tests, but its clinical significance is unclear. Because of the low number of adverse events, the authors were less certain whether paracetamol increases risk of serious adverse events. Paracetamol is widely considered the first choice for treating hip and knee pain due to osteoarthritis. However, this review confirms that the effect of paracetamol for immediate and short-term pain is minimal and probably not clinically relevant. Despite high-quality evidence demonstrating no risk of adverse events, paracetamol should be avoided in monotherapy for hip and knee osteoarthritis and other drugs should be preferred. The authors thank Cochrane Rehabilitation and Cochrane Musculoskeletal Group for reviewing the contents of the Cochrane Corner. The authors declare no conflicts of interest.

Osteoarthritis (OA) is a chronic joint disease characterized by cartilage destruction and periarticular osteophyte formation. One therapeutic option for this condition, the Wutou Decoction (WTD) Chinese medicine formula, is satisfactory in its efficacy. Here, we used bioinformatic and molecular docking techniques to investigate the mechanism of action of WTD in the treatment of OA. The active compounds (and their target proteins) of 5 Chinese herbs in WTD were obtained by searching the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The action targets of WTD for OA were obtained by searching the Therapeutic Target Database and by mining the microarray data in the Gene Expression Omnibus. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed to identify key targets for OA treatment with the help of Database for Annotation, Visualization, and Integrated Discovery. Based on the Cytoscape software version 3.6.1, the visual networks of the "TCM drugs-Active Compounds-Targets-Diseases" and protein-protein interaction of the key targets of WTD for the treatment of OA were constructed. The core active compounds and the key targets obtained were molecularly docked and validated. Analyses revealed 140 active compounds in WTD, 123 of which had a total of 163 corresponding targets. In addition, 331 differentially expressed genes and 227 OA-related targets were obtained. The interaction networks among 32 key targets were identified. The biological processes of WTD in treating OA mainly involved regulation of inflammatory factors, transcription of genetic materials, cell cycle, angiogenesis, and endocrine regulation. The signaling pathways involved mainly included TNF signaling pathway, rheumatoid arthritis signaling pathway, cancer-related signals, vascular endothelial growth factor signaling pathway, and osteoclast differentiation signaling pathways. Molecular docking showed that 7 core compounds including quercetin and kaempferol had strong affinities with key target proteins for the WTD treatment of OA. WTD with multi-component can treats OA through multi-pathway. Its active compounds, including quercetin and kaempferol, can exert their therapeutic effects on OA by acting on TNF, PTGS2, MMP2, IL-6, IL-1β, and other key targets to regulate inflammation, immunity, autophagy, and endocrine-related signaling pathways.

Background:Osteoarthritis (OA) remains one of the most common osteopathy for centuries, which can be attributed to multiple risk factors including mechanical and biochemical ones. More and more studies verified that inflammatory cytokines play important roles in the progression of OA, such as tumor necrosis factor-alpha (TNF-α). In this study, we aimed to investigate the relationship between epigenetic manifestations of TNF-? and the pathogenesis of OA.Methods:Totally, 37 OA patients’ cartilage was collected through the knee joint and 13 samples of articular cartilage as healthy control was collected through traumatic amputation. Real-time PCR, Western blot and ELISA analysis were performed to observe the expression of target genes and proteins in collected samples.Results:Compared with the healthy control group, TNF-? was over-expressing in cartilage which was collected from OA patients. DNA hypomethylation, histone hyperacetylation and histone methylation were observed in the TNF-? promoter in OA compared with normal patients, and we also studied series of enzymes associated with epigenetics. The results showed that by increasing DNA methylation and decreasing histone acetylation in the TNF-? promoter, and TNF-? over-expression in OA cartilage was suppressed, histone methylation has no significant correlation with OA.Conclusion:In conclusion, the changes of epigenetic status regulate TNF-α expression in the cells, which are pivotal to the OA disease process. These results may give us a better understanding of OA and may provide new therapeutic options.

n-3 polyunsaturated fatty acids alleviate the progression of obesity-related osteoarthritis and protect cartilage through inhibiting the HMGB1-RAGE/TLR4 signaling pathway