Inflammatory regulators play a fundamental role in the development of trigeminal neuralgia (TN). However, the precise mechanisms and causal relationship with the risk of TN remain poorly understood.

This study aimed to assess the causal relationship between 41 inflammatory cytokines and TN using Mendelian randomization (MR) analysis. A two-sample MR approach was utilized, employing genetic variation data on TN from a large publicly available genome-wide association study (GWAS) comprising 1777 cases of European ancestry and 360,538 controls. Additionally, summary data from a GWAS on inflammatory cytokines, comprising 8293 healthy participants, were utilized. The causal relationship between exposure and outcome was primarily assessed using the inverse variance weighted (IVW) method, accompanied by sensitivity analyses.

The study revealed an association between increased risk of TN and cutaneous T cell-attracting chemokine（CTACK） (odds ratio [OR] = 1.187; 95% confidence interval [CI], 1.041-1.35; p = 0.01) and interferon (IFN)-gamma（MIG） (OR = 1.232; 95% CI, 1.080-1.449; p = 0.01), while interleukin (IL)-16 (OR = 0.823; 95% CI, 0.685-0.989; p = 0.03) and interferon (IFN)-G (OR = 0.779; 95% CI, 0.612-0.992; p = 0.04) were associated with decreased risk of TN. Notably, no potential effect of TN on inflammatory factors was observed.

This study provides novel insights into the pathogenesis of TN, highlighting the crucial role of inflammatory cytokines in TN risk.

This study advances our understanding of TN by using MR to identify the causal roles of specific inflammatory cytokines. These results underscore the importance of inflammation in TN development and suggest potential targets for new treatments.

Liver fibrosis is a chronic liver injury resulting from factors like viral hepatitis, autoimmune hepatitis, non-alcoholic steatohepatitis, fatty liver disease, and cholestatic liver disease. Liver transplantation is currently the gold standard for treating severe liver diseases. However, it is limited by a shortage of donor organs and the necessity for lifelong immunosuppressive therapy. Mesenchymal stem cells (MSCs) can differentiate into various liver cells and enhance liver function when transplanted into patients due to their differentiation and proliferation capabilities. Therefore, it can be used as an alternative therapy for treating liver diseases, especially for liver cirrhosis, liver failure, and liver transplant complications. However, due to the potential tumorigenic effects of MSCs, researchers are exploring a new approach to treating liver fibrosis using extracellular vesicles (exosomes) secreted by stem cells. Many studies show that exosomes released by stem cells can promote liver injury repair through various pathways, contributing to the treatment of liver fibrosis. In this review, we focus on the molecular mechanisms by which stem cell exosomes affect liver fibrosis through different pathways and their potential therapeutic targets. Additionally, we discuss the advantages of exosome therapy over stem cell therapy and the possible future directions of exosome research, including the prospects for clinical applications and the challenges to be overcome.

Links between cathepsin K and the pathophysiology of osteoarthritis (OA) can be established, not least because of the overabundance of cathepsin K in the serum of OA patients and the upregulation of cathepsin K in degraded cartilage in animal models of OA. Chondrocytes, chondroclasts, or osteoclasts contribute to the accumulated cathepsin K at the diseased osteochondral junction. After a general presentation of OA and cartilage physiology, as well as its degradation processes, we describe the function of cathepsin K and its effect on cartilage degradation via type II collagen cleavage. An overview of the most promising cathepsin K inhibitors is then presented, together with their in vitro effects. Although intensive research on cathepsin K inhibitors initially focused on bone resorption, there is growing interest in the potential of these drugs to prevent cartilage degradation. In this review, we summarize the pre-clinical and clinical trials that support the use of cathepsin K inhibitors in the treatment of OA. To date, no molecules of this type are commercially available, although a few have undergone clinical trials, but we believe that the development of cathepsin K inhibitors could broaden the therapeutic arsenal for the treatment of OA.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by diverse clinical manifestations, including joint symptoms. Arthritis represents one of the earliest manifestations of SLE, profoundly affecting the quality of life for affected individuals, yet the underlying mechanisms of SLE-associated arthritis remain insufficiently investigated. The study aimed to investigate the impact of SLE exacerbation on arthritis using the MRL/lpr mouse model, which closely mimics human SLE manifestations.

In the present study, we evaluated the impact of SLE onset on knee joint degeneration by comparing arthritic phenotype and complex molecular alterations between 6 female 14-week-old MRL/lpr mice, which manifest SLE, and MRL/MpJ mice, which remain unaffected.

Our results demonstrated that MRL/lpr mice exhibited a more severe arthritic phenotype compared to MRL/MpJ mice, characterized by elevated Osteoarthritis Research Society International (OARSI) scores (P < 0.01), disrupted extracellular matrix metabolism, impaired chondrocyte proliferation and increased apoptosis. Notably, inflammatory cytokines proteins such as IL-1β and TNF-α (both P < 0.01), IL-18 and IL-6 (both P < 0.05), were significantly increased in articular cartilage of MRL/lpr mice, accompanied by increased expression of calcitonin gene-related peptide (CGRP) (P < 0.05), NETRIN-1, and NESTIN (both P < 0.01), indicating that SLE promotes inflammation response and sensory nerve ingrowth in the knee joint, contributing to the progression of arthritis. Mechanistic analysis revealed that SLE exacerbation intensified chondrocyte pyroptosis by upregulating pyroptotic-related proteins, including NLRP3, CASPASE-1, and gasdermin D (all P < 0.01), through the regulation of the nuclear factor erythroid 2-related factor (NRF-2)/KEAP-1 and nuclear factor kappa-B (NF-κB) pathway.

Collectively, our findings underscore the mechanistic connection between chondrocyte pyroptosis and arthritis exacerbation in SLE, suggesting potential therapeutic targets for mitigating arthritis progression in the context of SLE.

Previous cross-sectional studies have demonstrated that the body roundness index (BRI) is associated with knee osteoarthritis (KOA). However, no longitudinal studies have confirmed this association. This study aims to explore the link between BRI and KOA risk in the Chinese population through longitudinal analysis and to evaluate its utility in early diagnosis and risk prediction.

This study utilizes data from the China Health and Retirement Longitudinal Study (CHARLS). A total of 7,318 participants who were followed from 2015 to 2020 were included. BRI was calculated using physical examinations and questionnaire data, and participants were categorized by quartiles. The relationship between BRI and KOA risk was assessed using multivariate weighted regression models and trend tests, while subgroup and sensitivity analyses were conducted to ensure the robustness of the findings.

After 5 years of follow-up, 1,035 participants (14.14%) were diagnosed with KOA. Findings indicate a positive correlation between BRI and KOA risk (HR = 1.08, 95% CI: 1.02-1.13, p = 0.0039), with an increasing trend in KOA risk across BRI quartiles (p for trend = 0.0033). Subgroup analysis reveals that the association is particularly strong among individuals aged 50-59, males, those living in rural areas, and those without cardiovascular disease.

This study establishes that an increase in BRI significantly elevates KOA risk. These findings suggest that BRI could be an effective tool for KOA risk assessment and could contribute to the development of personalized prevention strategies. Additionally, BRI is valuable in elucidating the potential mechanisms linking body fat distribution and inflammatory responses in KOA progression.

Background/Objectives: The consumption of food rich in anthocyanins, a natural pigment found in plants, has been associated with improved joint health. However, systematic efforts to summarise the effects of anthocyanins and their deglycosylated forms, anthocyanidins, in managing osteoarthritis (OA) are lacking. This scoping review aims to comprehensively summarise the current evidence regarding the role of anthocyanins and anthocyanidins in OA management and highlights potential research areas. Methods: A comprehensive literature search was performed using PubMed, Scopus, and Web of Science in January 2025 to look for primary studies published in English, with the main objective of investigating the chondroprotective effects of anthocyanins and anthocyanidins, regardless of their study designs. Results: The seven included studies showed that anthocyanins and anthocyanidins suppressed the activation of inflammatory signalling, upregulated sirtuin-6 (cyanidin only), and autophagy (delphinidin only) in chondrocytes challenged with various stimuli (interleukin-1β, oxidative stress, or advanced glycation products). Anthocyanins also preserved cartilage integrity and increased the pain threshold in animal models of OA. No clinical trial was found in this field, suggesting a translation gap. Conclusions: In conclusion, anthocyanins and anthocyanidins are potential chondroprotective agents, but more investigations are required to overcome the gap in clinical translation.

Background/Objectives: Osteoarthritis (OA) is a very common degenerative joint disease that has a significant negative impact on patients' lives and which can lead to functional limitations and disability. Matrix metalloproteinase 13 (MMP-13) is a key enzyme responsible for the degenerative changes in cartilage occurring during the pathogenesis of OA. This cohort study analyzed the differences in the expression level of MMP13 mRNA in articular cartilage with subchondral bone and in the synovium of patients with OA, according to the disease stage, in order to develop potential markers for OA progression, as well as for the degree of pain perception, in order to discover a molecular biomarker related to pain. Methods: In thirty-one patients (n = 31), the expression level of the studied gene was assessed in the affected and unaffected areas of the knee joint using the qPCR method. Statistical analysis was performed using the Mann-Whitney U test, the Kruskal-Wallis test, and Spearman's rank correlation coefficient. Results: A significantly higher expression level of MMP13 mRNA was noticed in the OA-affected articular cartilage with subchondral bone compared to the control tissue (p = 0.027, Mann-Whitney U test). The expression level of MMP13 mRNA was higher in patients with stage 4 knee OA than in those with stage 3, but the difference in MMP13 mRNA expression level was statistically insignificant (p > 0.05, Mann-Whitney U test). A higher MMP13 mRNA expression level was noticed in the OA-affected synovium compared to the control tissue (median RQ: 0.068 and 0.037, respectively), but these differences were not significant (p > 0.05, Mann-Whitney U test). A significantly higher MMP13 mRNA expression level was observed in the synovium of stage 4 knee OA patients compared to stage 3 patients (p = 0.015, Mann-Whitney U test). There was no significant difference in the expression level of MMP13 mRNA between both tissues, i.e., the articular cartilage with subchondral bone and the synovium from the stage 3 group and the control tissue (p > 0.05, Mann-Whitney U test); however, a significant difference was found between these tissues in stage 4 and in the control tissue (p = 0.014, Mann-Whitney U test). Conclusions: The results of our pilot study indicated the diagnostic potential of MMP13 mRNA and proved its role in the development and progression of OA. Further studies are needed to verify the potential utility of MMP13 mRNA in the development of molecularly targeted therapy for patients with OA.

This study aims to assess the effectiveness and safety of mesenchymal stem cell (MSC) transplantation in the treatment of autoimmune and rheumatic immune diseases through randomized controlled trials (RCTs).

Two researchers conducted a comprehensive search of Chinese and English databases from their inception until Dec. 2023. The literature screening and data extraction were then performed. Statistical analysis was carried out using RevMan 5.4 software.

A total of 42 relevant RCTs, involving 2,183 participants, were ultimately included in this study. These RCTs encompassed four types of rheumatic immune and bone diseases, namely rheumatoid arthritis (RA), osteoarthritis (OA), spondyloarthritis, systemic sclerosis arthritis, systemic lupus erythematosus (SLE), inflammatory bowel disease, multiple sclerosis, primary Sjögren's syndrome (PSS). The systematic review indicates that MSC transplantation may improve spondyloarthritis, RA, PSS. The meta-analysis reveals that MSC transplantation significantly improved symptoms in patients with OA [VAS (visual analogue scale): bone marrow: SMD = - 0.95, 95% CI - 1.55 to - 0.36, P = 0.002; umbilical cord: SMD = - 1.25, 95% CI - 2.04 to - 0.46, P = 0.002; adipose tissue: SMD = -1.26, 95% CI -1.99 to - 0.52, P = 0.0009)], SLE [Systemic lupus erythematosus disease activity index (SLEDAI): SMD = - 2.32, 95% CI - 3.59 to - 1.06, P = 0.0003], inflammatory bowel disease [clinical efficacy: RR = 2.02, 95% CI 1.53 to 2.67, P < 0.00001]. However, MSC transplantation may not improve the symptoms of multiple sclerosis and systemic sclerosis (Ssc). Importantly, MSC transplantation did not increase the incidence of adverse events (OA: RR = 1.23, 95% CI 0.93 to 1.65, P = 0.15; SLE: RR = 0.83, 95% CI 0.28 to 2.51, P = 0.76; Inflammatory bowel disease: RR = 0.99, 95% CI 0.81 to 1.22, P = 0.96; Multiple sclerosis: RR = 1.12, 95% CI 0.81 to 1.53, P = 0.50), supporting its safety profile across the included studies. These findings suggest that MSC transplantation holds promise for several rheumatic and autoimmune diseases while highlighting areas where further research is warranted.

MSC transplantation may have the potential to treat autoimmune and rheumatic immune diseases. Moreover. MSC transplantation appears to be relatively safe and could be considered as a viable alternative treatment option for autoimmune and rheumatic immune diseases.

Osteoarthritis (OA) is characterized by the progressive degeneration of the synovial joint, leading to irreversible damage to articular cartilage and subchondral bone. While animal models have advanced our understanding of OA, numerous unresolved issues still remain. The zebrafish, known for its transparent body, rapid developmental, and impressive regenerative capabilities, offers substantial potential for osteoarthritis research. This study seeks to establish a new OA model utilizing the zebrafish jaw joint, acting as a supplement to traditional animal models. In the future, this model could serve as a valuable platform for delving deeper into the mechanisms of this disease, as well as for advancing drug discovery and therapeutic interventions. Leveraging the skeletal structure of zebrafish, we targeted the largest jaw joint for our research. A custom fixation device was crafted, and a microinjection system was utilized to inject mono-iodoacetate (MIA) or collagenase type II (CTII) into the joint cavity of zebrafish. Subsequent analyses included histological staining, immunohistochemistry, OA research society international (OARSI) scoring, and real-time in vivo imaging were performed at 7, 14, and 28 days post injection. Our results effectively demonstrated the presence of synovial inflammation and cartilage damage within the zebrafish mandible, affirming the feasibility of inducing OA in zebrafish. In conclusion, the local injection of chemical agents into the joint cavity of zebrafish effectively induced the occurrence of OA. Establishing the zebrafish OA model enhances the array of animal models available for OA research. Moreover, zebrafish present distinct advantages, including robust regenerative abilities, genetic editing simplicity, and efficient drug screening. Consequently, this offers a fresh avenue for investigating the pathogenesis, prevention, and potential therapeutic approaches for human OA.

The ketogenic diet (KD) has demonstrated efficacy in ameliorating inflammation in rats with osteoarthritis (OA). However, the long-term safety of the KD and the underlying mechanism by which it delays OA remain unclear. We found that while long-term KD could ameliorate OA, it induced severe hepatic steatosis in mice. Consequently, we developed 2 versions of ketogenic-based diets: KD supplemented with vitamin D and intermittent KD. Both KD supplemented with vitamin D and intermittent KD effectively alleviated OA by significantly reducing the levels of inflammatory cytokines, cartilage loss, sensory nerve sprouting, and knee hyperalgesia without inducing hepatic steatosis. Furthermore, β-hydroxybutyrate (β-HB), a convenient energy carrier produced by adipocytes, could ameliorate OA without causing liver lesions. Mechanistically, β-HB enhanced chondrocyte autophagy and reduced apoptosis through the activation of Erb-B2 receptor tyrosine kinase 3 (ERBB3) signaling pathway; a pathway which was down-regulated in the articular chondrocytes from both OA patients and mice. Collectively, our findings highlighted the potential therapeutic value of β-HB and KD supplemented with vitamin D and intermittent KD approaches for managing OA.

Schizophrenia is a complex and heterogenous psychiatric disorder characterized by positive, negative, and cognitive symptoms. Our previous study identified three subgroups of schizophrenia patients based on plasma microRNA (miRNA) profiles. The present study aims to (1) verify the reproducibility of the miRNA-based patient stratification and (2) explore the pathophysiological pathways linked to the symptoms using plasma miRNAs. We measured levels of 376 miRNAs in plasma samples of schizophrenia patients and obtained their Positive and Negative Syndrome Scale (PANSS) scores and the Brief Assessment of Cognition in Schizophrenia (BACS) scores. The plasma miRNA profiles identified similar subgroups of patients as in the previous study, suggesting miRNA-based patient stratification is potentially reproducible. Our multivariate analysis identified optimal combinations of miRNAs to estimate the PANSS positive and negative subscales and BACS composite scores. Those miRNAs consistently enriched 'inflammation' and 'NFκB1' according to miRNA set enrichment analysis. Our literature-based text mining and survey confirmed that those miRNAs were associated with IL-1β, IL-6, and TNFα, suggesting that exacerbated positive, negative, and cognitive symptoms are associated with high inflammation. In conclusion, miRNAs are a potential biomarker to identify patient subgroups reflecting pathophysiological conditions and to investigate symptom-related molecular mechanisms in schizophrenia.

Campylaephora hypnaeoides (C. hypnaeoides) was extracted using fermented ethanol. The effect of fermented ethanol extract of C. hypnaeoides (FeCH) on chondrocyte viability was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-iphenyltetrazolium bromide assay, which showed no cytotoxicity at 2 mg/mL. FeCH pretreatment in IL-1β-stimulated chondrocytes significantly inhibited the accumulation of nitric oxide and prostaglandin E2, which was analyzed using the ELISA assay. In addition, protein expression levels of inflammatory-related factors, such as inducible nitric oxide synthase, cyclooxygenase-2, interleukin-6, tumor necrosis factor-alpha, and cartilage-degrading-related enzymes, such as matrix metalloproteinases-1, -3, and -13, and a disintegrin and metalloproteinase with thrombospondin motifs-4 and -5 were significantly decreased in IL-1β-stimulated chondrocytes pretreated with FeCH, which were analyzed using western blot analysis. In addition, as a result of analyzing the content of collagen type II (Col II) and proteoglycan through western blot analysis and alcian blue staining, FeCH pretreatment prevented the degradation of Col II and proteoglycan. It was analyzed through western blot analysis that the chondroprotective effect of FeCH may be mediated through MAPKs and NF-κB-signaling mechanisms. In an in vivo study, an osteoarthritis experimental animal model with damaged medial meniscus (DMM) was utilized and orally administered daily for 8 weeks after surgery. At the study end point, knee joints were harvested and subjected to histological analysis with safranin O staining. As a result, articular cartilage was significantly protected in the FeCH group compared to the DMM group. These results suggest FeCH as a candidate material for the development of pharmaceutical materials for the treatment or prevention of degenerative arthritis.

Better prediction of outcome after total hip arthroplasty (THA) is warranted. Systemic inflammation and central neuroinflammation are possibly involved in progression of osteoarthritis and pain. We explored whether inflammatory biomarkers in blood and cerebrospinal fluid (CSF) were associated with clinical outcome, and baseline pain or disability, 12 months after THA.

A total of 50 patients from the Danish Pain Research Biobank (DANPAIN-Biobank) between January and June 2018 were included. Postoperative outcome was assessed as change in Oxford Hip Score (OHS) from baseline to 12 months after THA, pain was assessed on a numerical rating scale, and disability using the Pain Disability Index. Multiple regression models for each clinical outcome were included for biomarkers in blood and CSF, respectively, including age, sex, BMI, and Kellgren-Lawrence score.

Change in OHS was associated with blood concentrations of tumour necrosis factor (TNF), interleukin-8 (IL-8), interleukin-6 receptor (IL-6R), glycoprotein 130 (gp130), and IL-1β (R2 = 0.28, p = 0.006), but not with CSF biomarkers. Baseline pain was associated with blood concentrations of lymphotoxin alpha (LTα), TNFR1, TNFR2, and IL-6R (R2 = 0.37, p < 0.001) and CSF concentrations of TNFR1, TNFR2, IL-6, IL-6R, and IL-1Ra (R2 = 0.40, p = 0.001). Baseline disability was associated with blood concentrations of TNF, LTα, IL-8, IL-6, and IL-1α (R2 = 0.53, p < 0.001) and CSF concentrations of gp130, TNF, and IL-1β (R2 = 0.26, p = 0.002). Thus, preoperative systemic low-grade inflammation predicted 12-month postoperative outcome after THA, and was associated with preoperative pain and disability.

This study highlights the importance of systemic inflammation in osteoarthritis, and presents a possible path for better patient selection for THA in the future. Preoperative central neuroinflammation was associated with preoperative pain and disability, but not change in OHS after THA.

The study aimed to determine the level of health literacy in patients with knee osteoarthritis and investigate the relationship between health literacy and exercise approaches and physical therapy use.

The cross-sectional study included 203 patients (143 females, 60 males; mean age: 63.5±9.2 years) between November 2018 and September 2019. Sociodemographic data, exercise habits, the number of applications to the physical medicine and rehabilitation outpatient clinic, and physical therapy applications were recorded. The Turkish Health Literacy Scale-32 (THLS-32), was used to determine health literacy. The Western Ontario and McMaster Universities Arthritis Index (WOMAC) was used to evaluate pain and physical function. The relationship between THLS-32 and the number of admissions to the outpatient clinic, the number of physical therapy applications, exercise frequency, and WOMAC scores were investigated.

The median THLS-32 of the patients was 33.8 (13-46.8). A statistically significant negative correlation was found between THLS-32 scores and the number of admissions to the physical medicine and rehabilitation outpatient clinic for knee pain in the last year, the number of physical therapies, the exercise frequency, and total WOMAC scores.

Increasing health literacy strengthens the capacities and participation of patients, reduces the costs of physical therapy, as well as medication costs, and consequently increases efficiency in the use of health services.

Organ-on-a-chip, also known as "tissue chip," is an advanced platform based on microfluidic systems for constructing miniature organ models in vitro. They can replicate the complex physiological and pathological responses of human organs. In recent years, the development of bone and joint-on-chip platforms aims to simulate the complex physiological and pathological processes occurring in human bones and joints, including cell-cell interactions, the interplay of various biochemical factors, the effects of mechanical stimuli, and the intricate connections between multiple organs. In the future, bone and joint-on-chip platforms will integrate the advantages of multiple disciplines, bringing more possibilities for exploring disease mechanisms, drug screening, and personalized medicine. This review explores the construction and application of Organ-on-a-chip technology in bone and joint disease research, proposes a modular construction concept, and discusses the new opportunities and future challenges in the construction and application of bone and joint-on-chip platforms.

The relationship among inflammation, pain, and cognitive decline in osteoarthritis (OA) patients is complex and has not been sufficiently explored; therefore, we undertook this research to evaluate how OA-related inflammation and pain affect cognitive functions, as well as to examine the potential of urinary markers as indicators of these conditions. This study examined fifty OA patients through clinical and cognitive assessments, morphological analyses, urinary biomarkers, and bioinformatics. Morphologically, 24% of patients had moderate to high synovial inflammation, which was significantly correlated with depressive symptoms, pain intensity, and self-reported anxiety. The Montreal Cognitive Assessment indicated minimal decline in most patients but showed negative correlations with age and inflammation severity. Urinary TNF-α and TGF-β1 levels positively correlated with body mass index and pain and synovitis score and immune cell infiltration, respectively. In contrast, cartilage oligomeric matrix protein and C-telopeptides of type II collagen showed inverse correlations with pain duration and cognitive function, respectively. Distinct patient clusters with higher inflammation were identified and were associated with reported pain and depressive symptoms. Urinary TNF-α and TGF-β1 can serve as biomarkers reflecting inflammation and disease severity in OA. This study suggests that synovial inflammation may be linked to mental and cognitive health in some patient cohorts.

Osteoarthritis (OA) is a significant contributor to pain and disability worldwide. Pain is the main complaint of OA patients attending the clinic and has a large impact on their quality of life and economic standards. However, existing treatments for OA-related pain have not been shown to achieve good relief. The main focus is on preventing and slowing the progression of OA so that the problem of OA pain can be resolved. Pain caused by OA is complex, with the nature, location, duration, and intensity of pain changing as the disease progresses. Previous research has highlighted the role of various forms of cell death, such as apoptosis and necrosis, in the progression of pain in OA. Emerging studies have identified additional forms of novel cell death, such as pyroptosis, ferroptosis, and necroptosis that are linked to pain in OA. Different types of cell death contribute to tissue damage in OA by impacting inflammatory responses, reactive oxygen species (ROS) production, and calcium ion levels, ultimately leading to the development of pain. Evidence suggests that targeting novel types of cell death could help alleviate pain in OA patients. This review delves into the complex mechanisms of OA pain, explores the relationship between different modes of novel cell death and pain, and proposes novel cell death as a viable strategy for the treatment of these conditions, with the goal of providing scientific references for the development of future OA pain treatments and drugs.

Bisphosphonates (BP) are considered a treatment option for osteoarthritis (OA) due to reduction of OA-induced microtrauma in the bone marrow, stabilization of subchondral bone (SB) layer and pain reduction. The effects of high-dose alendronate (ALN) treatment on SB and articular cartilage after destabilization of the medial meniscus (DMM) or Sham surgery of male C57Bl/6J mice were analyzed. We performed serum analysis; histology and immunohistochemistry to assess the severity of OA and a possible pain symptomatology. Subsequently, the ratio of bone volume to total volume (BV/TV), epiphyseal trabecular morphology and the bone mineral density (BMD) was analyzed by nanoCT. Serum analysis revealed a reduction of ADAMTS5 level. The histological evaluation displayed no protective effect of ALN-treatment on cartilage erosion. NanoCT-analysis of the medial epiphysis revealed an increase of BV/TV in ALN-treated mice. Only the DMM group had significantly higher SB volume accompanied by decreased subchondral bone surface. Furthermore Nano-CT analysis revealed an increase in trabecular density and number, a decreased BMD and reduced osteophyte formation in the ALN mice. ALN treatment affected bone micro-architecture by reducing osteophytosis with simultaneous increasing subchondral bone plate thickness, trabecular thickness and BMD. Accordingly, ALN cannot be considered as a potential treatment strategy in general, however in a subgroup of patients with high bone turnover in an early-stage of OA, ALN might be an option when applied during a restricted time frame.

Osteoarthritis (OA) is the most common form of arthritis and the leading musculoskeletal disorders in adults. Modified Simiao Powder (MSMP) has been widely used in the treatment of OA with remarkable clinical ecaciousness.

This study aimed to elucidate underlying mechanisms of MSMP in OA by employing network pharmacology, molecular docking, and molecular dynamics simulations, due to the unclear mode of action.

Bioinformatic analysis was used to evaluate the major chemical constituents of MSMP, determine prospective target genes, and screen genes associated with OA. Network pharmacology methods were then applied to identify the crucial target genes of MSMP in OA treatment. Further analyses included gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. These key targets within the pertinent pathways was further confirmed by molecular docking, binding energy evaluation, and molecular dynamics simulations.

Network pharmacology analysis identified an MSMP component-target-pathway network comprising 11 central active compounds, 25 gene targets, and 12 biological pathways.

These findings imply that the therapeutic effects of MSMP was potentially mediated by targeting several pivotal genes, such as androgen receptor (AR), NFKB1, AKT1, MAPK1, and CASP3, and regulating some pathways, including lipid metabolism and atherosclerosis, the AGE-RAGE signaling pathway in diabetic complications, the PI3K-Akt signaling pathway, fluid shear stress, atherosclerosis, and Kaposi's sarcoma-associated herpesvirus infection. Molecular docking assessments demonstrated that these compounds of MSMP, such as berberine, kaempferol, quercetin, and luteolin, exhibit high binding anities to AR and AKT1. Molecular dynamics simulations validated the interactions between these compounds and targets.

The therapeutic effect of MSMP likely attributed to the modulation of multiple pathways, including lipid metabolism, atherosclerosis, the AGE-RAGE signaling pathway, and the PI3K-Akt signaling pathway, by the active components such as berberine, kaempferol, luteolin, and quercetin. Especially, their actions on target genes like AR and AKT1 contribute to the therapeutic benefits of MSMP observed in the treatment of OA.

Osteoarthritis (OA) affects 528 million individuals globally, predominantly in knee and hip joints, with a notable impact on females aged over 55, resulting in a substantial economic burden. However, the efficacy of modalities used in physiotherapy to manage OA pain for reducing the need for joint replacement remains an open question, and guidelines differ. Our systematic narrative review, drawing from reputable databases (e.g., PubMed, Cochrane, and CINAHL) with specific Mesh terms investigated evidence from 23 Randomized Controlled Trials (that included a control or a sham group in 30 different protocols) using therapeutic modalities like ultrasound, diathermy, and electrical stimulation for knee and hip OA pain, involving a total of 1055 subjects. We investigated the attainment of minimal clinically important differences in pain reduction, operationalized through a 20% decrement in the Western Ontario and McMaster University Arthritis Index or Visual Analog Scale (VAS) score. Our results indicated that 15 protocols out of 30 reach that level, but there were no statistical differences among modalities. Half of the protocol presented in the literature reached clinical efficiency but studies on hip remains scarce. We recommend a comprehensive, sequential, and multimodal intervention plan for individuals with joint OA with initial transcutaneous electrical nerve stimulation and progressing to a 2-week protocol of continuous ultrasound, potentially combined with deep microwave diathermy. Long-term intervention involves the use of pulsed electrical stimulation. For hip OA, a cautious approach and discussions with healthcare providers about potential benefits of spinal cord nerve stimulation.

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage breakdown and chronic inflammation in joints. As the most prevalent form of arthritis, OA affects around 600 million people globally. Despite the increasing number of individuals with OA risk factors, such as aging and obesity, there is currently no effective cure for the disease. In this context, this study investigated the therapeutic effects of tamarixetin, a flavonoid with antioxidative and anti-inflammatory properties, against OA pathology and elucidated the underlying molecular mechanism. In interleukin-1β (IL-1β)-treated chondrocytes, tamarixetin inhibited the OA phenotypes, restoring cell viability and chondrogenic properties while reducing hypertrophic differentiation and dedifferentiation. Tamarixetin alleviated oxidative stress via the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation and inhibited mitogen-activated protein kinase and nuclear factor-κB (NF-κB). Furthermore, tamarixetin attenuated pyroptosis, a programmed cell death caused by excessive inflammation, by suppressing inflammasome activation. We confirmed that the chondroprotective effects of tamarixetin are mediated by the concurrent upregulation of Nrf2 signaling and downregulation of NF-κB signaling, which are key players in balancing antioxidative and inflammatory responses. Overall, our study demonstrated that tamarixetin possesses chondroprotective properties by alleviating IL-1β-induced cellular stress in chondrocytes, suggesting its therapeutic potential to relieve OA phenotype.

.In this study, we investigated the potential of meloxicam (MLX) developed as transferosomal gel as a novel lipidic drug delivery system to address osteoarthritis (OTA), a degenerative joint disease that causes pain and stiffness. By incorporating meloxicam into a transferosomal gel, our aim was to provide a targeted and efficient delivery system capable of alleviating symptoms and slowing down the progression of OTA.

Classical lipid film hydration technique was utilized to formulate different transferosomal formulations. Different transferosomal formulations were prepared by varying the molar ratio of phospholipon-90H (phosphodylcholine) to DSPE (50:50, 60:40, 70:30, 80:20, and 90:10) and per batch, 80mg of total lipid was used. The quality control parameters such as entrapment efficiency, particle size and morphology, polydispersity and surface electric charge, in vitro drug release, ex vivo permeation and stability were measured.

The optimized transferosomal formulations revealed a small vesicle size (121±12nm) and greater MLX entrapment (68.98±2.3%). Transferosomes mediated gel formulation MLX34 displayed pH (6.3±0.2), viscosity (6236±12.3 cps), spreadability (13.77±1.77 gm.cm/sec) and also displayed sustained release pattern of drug release (81.76±7.87% MLX released from Carbopol-934 gel matrix in 24h). MLX34 revealed close to substantial anti-inflammatory response, with ∼81% inhibition of TNF-α in 48h. Physical stability analysis concluded that refrigerator temperature was the preferred temperature to store transferosomal gel.

MLX loaded transferosomes containing gel improved the skin penetration and therefore resulted into increased inhibition of TNF-α level.

Anterior cruciate ligament injury and anterior cruciate ligament reconstruction (ACLR) are risk factors for symptomatic posttraumatic osteoarthritis (PTOA). After ACLR, individuals demonstrate altered joint tissue metabolism indicative of increased inflammation and cartilage breakdown. Serum biomarker changes have been associated with tibiofemoral cartilage composition indicative of worse knee joint health but not with PTOA-related symptoms.

The purpose of this study was to determine associations between changes in serum biomarker profiles from the preoperative sample collection to 6 months after ACLR and clinically relevant knee PTOA symptoms at 12 months after ACLR. It was hypothesized that increases in biomarkers of inflammation, cartilage metabolism, and cartilage degradation would be associated with clinically relevant PTOA symptoms after ACLR.

Case-control study; Level of evidence, 3.

Individuals undergoing primary ACLR were included (N = 30). Serum samples collected preoperatively and 6 months after ACLR were processed to measure markers indicative of changes in inflammation (ie, monocyte chemoattract protein 1 [MCP-1]) and cartilage breakdown (ie, cartilage oligomeric matrix protein [COMP], matrix metalloproteinase 3, ratio of type II collagen breakdown to type II collagen synthesis). Knee injury and Osteoarthritis Outcome Score surveys were completed at 12 months after ACLR and used to identify participants with and without clinically relevant PTOA-related symptoms. K-means cluster analyses were used to determine serum biomarker profiles. One-way analyses of variance and logistic regressions were used to assess differences in Knee injury and Osteoarthritis Outcome Score subscale scores and clinically relevant PTOA-related symptoms between biomarker profiles.

Two profiles were identified and characterized based on decreases (profile 1: 67% female; age, 21.4 ± 5.1 years; body mass index, 24.4 ± 2.4) and increases (profile 2: 33% female; age, 21.3 ± 3.2 years; body mass index, 23.4 ± 2.6) in sMCP-1 and sCOMP preoperatively to 6 months after ACLR. Participants with profile 2 did not demonstrate differences in knee pain, symptoms, activities of daily living, sports function, or quality of life at 12 months after ACLR compared to those with profile 1 (P = .56-.81; η2 = 0.002-0.012). No statistically significant associations were noted between biomarker profiles and clinically relevant PTOA-related symptoms (odds ratio, 1.30; 95% CI, 0.23-6.33).

Serum biomarker changes in MCP-1 and sCOMP within the first 6 months after ACLR were not associated with clinically relevant PTOA-related symptoms.

Osteoarthritis (OA) is a chronic degenerative disease characterized by overall joint tissue damage. Metformin (Met) has been shown to inhibit inflammatory reactions, though its potential protective mechanism on cartilage remains unclear. This study investigated Met's potential to protect cartilage in an OA rat model. Various morphological experiments were conducted to assess changes in cartilage tissue morphology before and after Met treatment. Protein and mRNA levels of cartilage-specific genes were measured using western blot, immunohistochemical staining, and RT-qPCR. Additionally, protein levels of autophagy-related and mTOR pathway-related proteins were measured. The results indicate an imbalance in the synthesis and degradation metabolism of chondrocytes, downregulation of cellular autophagy, and activation of the PI3K/Akt/mTOR pathway after surgery. However, treatment with Met could upregulate the expression of synthetic metabolic factors, indicating its contribution to cartilage repair. Furthermore, analysis of autophagy and pathway protein levels indicated that Met effectively attenuated autophagic damage to osteoarthritic cartilage cells and abnormal activation of the PI3K/Akt/mTOR pathway. In conclusion, Met can inhibit the abnormal activation of the PI3K/AKT/mTOR signaling pathway in cartilage tissue, promote the restoration of cartilage cell autophagic function, improve the balance of cartilage cell synthesis and degradation metabolism, and thus exert a protective effect on rat joint cartilage.

Chronic stress enhances the risk of neuropsychiatric disorders and contributes to the aggravation and chronicity of pain. The development of stress-associated diseases, including pain, is affected by individual vulnerability or resilience to stress, although the mechanisms remain elusive. We used the repeated social defeat stress model promoting susceptible and resilient phenotypes in male and female mice and induced knee mono-arthritis to investigate the impact of stress vulnerability on pain and immune system regulation. We analyzed different pain-related behaviors, measured blood cytokine and immune cell levels, and performed histological analyses at the knee joints and pain/stress-related brain areas. Stress susceptible male and female mice showed prolonged arthritis-associated hypersensitivity. Interestingly, hypersensitivity was exacerbated in male but not female mice. In males, stress promoted transiently increased neutrophils and Ly6Chigh monocytes, lasting longer in susceptible than resilient mice. While resilient male mice displayed persistently increased levels of the anti-inflammatory interleukin (IL)-10, susceptible mice showed increased levels of the pro-inflammatory IL-6 at the early- and IL-12 at the late arthritis stage. Although joint inflammation levels were comparable among groups, macrophage and neutrophil infiltration was higher in the synovium of susceptible mice. Notably, only susceptible male mice, but not females, presented microgliosis and monocyte infiltration in the prefrontal cortex at the late arthritis stage. Blood Ly6Chigh monocyte depletion during the early inflammatory phase abrogated late-stage hypersensitivity and the associated histological alterations in susceptible male mice. Thus, recruitment of blood Ly6Chigh monocytes during the early arthritis phase might be a key factor mediating the persistence of arthritis pain in susceptible male mice. Alternative neuro-immune pathways that remain to be explored might be involved in females.

In the realm of studying joint-related diseases, there is a continuous quest for more accurate and representative models. Recently, regenerative medicine and tissue engineering have seen a growing interest in utilizing organoids as powerful tools for studying complex biological systems in vitro. Organoids, three-dimensional structures replicating the architecture and function of organs, provide a unique platform for investigating disease mechanisms, drug responses, and tissue regeneration. The surge in organoid research is fueled by the need for physiologically relevant models to bridge the gap between traditional cell cultures and in vivo studies. Osteochondral organoids have emerged as a promising avenue in this pursuit, offering a better platform to mimic the intricate biological interactions within bone and cartilage. This review explores the significance of osteochondral organoids and the need for their development in advancing our understanding and treatment of bone and cartilage-related diseases. It summarizes osteochondral organoids' insights and research progress, focusing on their composition, materials, cell sources, and cultivation methods, as well as the concept of organoids on chips and application scenarios. Additionally, we address the limitations and challenges these organoids face, emphasizing the necessity for further research to overcome these obstacles and facilitate orthopedic regeneration.

Osteoarthritis (OA) related pain has affected millions of people worldwide. However, the current pharmacological options for managing OA-related pain have not achieved a satisfactory effect.

This narrative review provides an overview of the current and emerging drugs for OA-related pain. It covers the drugs' mechanism of action, safety, efficacy, and limitations. The National Library of Medicine (PubMed) database was primarily searched from 2000 to 2024.

Current treatment options are limited and suboptimal for OA pain management. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are the recognized and first-line treatment in the management of OA-related pain, and other drugs are inconsistent recommendations by guidelines. Emerging treatment options are promising for OA-related pain, including nerve growth factor (NGF) inhibitors, ion channel inhibitors, and calcitonin gene-related peptide (CGRP) antagonists. Besides, drugs repurposing from antidepressants and antiepileptic analgesics are shedding light on the management of OA-related pain. The management of OA-related pain is challenging as pain is heterogeneous and subjective. A more comprehensive strategy combined with non-pharmacological therapy needs to be considered, and tailored management options to individualized patients.

This study assessed the association between arthritis, functional impairment, and nutritional risk (NR). Cross-sectional data were from the Canadian Longitudinal Study on Aging, a nationally representative sample of 45-85-year-old community-dwelling Canadians (n = 41,153). The abbreviated Seniors in the Community: Risk Evaluating for Eating and Nutrition II (SCREEN II-AB) Questionnaire determined NR scores (continuous), and high NR (score < 38); the Older American Resources and Services scale measured functional impairment. NR scores and status (low/high) were modelled using multiple linear and logistic regressions, respectively. Analyses adjusted for demographic characteristics, functional impairment, and health (body mass index, self-rated general and mental health). Additional analyses stratified the models by functional impairment. People with arthritis had poorer NR scores (B: - 0.35, CI - 0.48, - 0.22; p < 0.05) and increased risks of high NR (OR 1.11, 95% CI 1.06, 1.17). Among those with functional impairment, the likelihood of high NR was 31% higher in people with arthritis compared to those without arthritis (95% CI 1.12, 1.53). Among those with no functional impairment, the likelihood of high NR was 10% higher in people with arthritis compared to those without (95% CI 1.04, 1.16). These relationships differed based on the type of arthritis. Arthritis is associated with high NR in community-dwelling older adults, both with and without functional impairment. Findings highlight the need for further research on these relationships to inform interventions and improve clinical practices.

This study aimed to compare the efficacy of intra-articular prolotherapy (IG) combined with peri-articular perineural injection (PG) in the management of knee osteoarthritis (KOA).

A total of 60 patients with the diagnosis of KOA were included in this double-blinded randomized controlled clinical trials. The inclusion criteria were as follow: (1) 48-80 years old; (2) the diagnose of KOA; (3) the grade 2 and 3 of the Kellgern-Lawrence grading scale; (4) the pain, crepitation, and knee joint stiffness continuing for 3 months at least. The main exclusion criteria were as follow: (1) any infection involving the knee skin; (2) history of any Influencing factors of disease. All patients were divided into three groups and received either IG, PG and I + PG under the ultrasound guidance and the 2, 4 and 8 weeks follow-up data of patients were available. (IG n = 20 or PG n = 20, I + PG n = 20). Visual Analogue Scale (VAS), The Western Ontario McMaster University Osteoarthritis Index (WOMAC) and the pressure pain threshold (PPT) were used as outcome measures at baseline, 2, 4 and 8 weeks.

There were no statistically significant differences in terms of age, sex, BMI, duration of current condition and baseline assessments of pain intensity, WOMAC scores and PPT. After treatment, the improvement of VAS activity, WOMAC and PPT values was showed compared with pre-treatment in all groups (p < 0.05). At 4 and 8 weeks after treatment, the VAS and WOMAC scores of the I + PG were significantly lower than those of the PG or IG, and the difference was statistically significant (p < 0.05). The PPT values of PG and I + PG were significantly improved compared to IG at 2, 4, and 8 weeks after treatment.

The ultrasound guided I + PG of 5% glucose seem to be more effective to alleviate pain and improve knee joint function than single therapy in short term. Clinical rehabilitators could clinically try this combination of I + PG to improve clinical symptoms in patients with KOA.

Pain is the major symptom of osteoarthritis (OA) and is an important factor in strategies to manage this disease. However, the current standard of care does not provide satisfactory pain relief for many patients. The pathophysiology of OA is complex, and its presentation as a clinical syndrome is associated with the pathologies of multiple joint tissues. Treatment options are generally classified as pharmacologic, nonpharmacologic, surgical, and complementary and/or alternative, typically used in combination to achieve optimal results. The goals of treatment are the alleviation of symptoms and improvement in functional status. Several studies are exploring various directions for OA pain management, including tissue regeneration techniques, personalized medicine, and targeted drug therapies. The aim of the present narrative review is to extensively describe all the treatments available in the current practice, further describing the most important innovative therapies. Advancements in understanding the molecular and genetic aspects of osteoarthritis may lead to more effective and tailored treatment approaches in the future.

Obesity-related joint pain is a common and debilitating condition that significantly impacts the quality of life, primarily due to the excess weight straining the joints. This results in inflammation and degeneration, which can cause pain, stiffness, and difficulty moving. We aimed to comprehensively review the literature discussing surgical interventions for obesity-related joint pain. We searched across databases (PubMed, Scopus, and Cochrane Library) to identify studies published between 2000 and 2023 that assessed surgical interventions for obesity-related joint pain. This review highlights the complex interplay of mechanical, inflammatory, and metabolic factors contributing to joint pain in obese individuals, highlighting both surgical and non-surgical interventions. Non-surgical interventions include weight loss, exercise, physical therapy, and medications. Surgical interventions include bariatric surgery and joint replacement surgery. Bariatric surgery significantly reduces body weight and improves the quality of life outcomes; however, multiple studies have found no improvement or worsening of joint pain post-surgery. Total joint arthroplasty has demonstrated good improvement in pain and function outcomes based on recent meta-analyses, although risks of complications are higher in obese patients. The treatment choice for obesity-related joint pain depends on the individual patient's circumstances. Non-surgical interventions are usually the first line of treatment. However, if these interventions are not effective, surgical interventions may be an option.

Osteoarthritis (OA) is characterized by cartilage damage, inflammation, and pain. Vascular endothelial growth factor receptors (VEGFRs) have been associated with OA severity, suggesting that inhibitors targeting these receptors alleviate pain (via VEGFR1) or cartilage degeneration (via VEGFR2). We have developed a nanoparticle-based formulation of pazopanib (Votrient), an FDA-approved anticancer drug that targets both VEGFR1 and VEGFR2 (Nano-PAZII). We demonstrate that a single intraarticular injection of Nano-PAZII can effectively reduce joint pain for a prolonged time without substantial side effects in two different preclinical OA rodent models involving either surgical (upon partial medial meniscectomy) or nonsurgical induction (with monoiodoacetate). The injection of Nano-PAZII blocks VEGFR1 and relieves OA pain by suppressing sensory neuronal ingrowth into the knee synovium and neuronal plasticity in the dorsal root ganglia and spinal cord. Simultaneously, the inhibition of VEGFR2 reduces cartilage degeneration. These findings provide a mechanism-based disease-modifying drug strategy that addresses both pain symptoms and cartilage loss in OA.

A topical medical device, AI500®, constituted of a single-chain polypeptide embedded in hyaluronic acid, was tested and evaluated in patients with reduced knee function due to osteoarthritis and other knee conditions. A total of 35 participants with reduced knee function assessed by the WOMAC Physical Function score were recruited. Four study visits were planned, from the first application at V0 to 1 week follow up at V3. Patient symptomatology was evaluated after 24 h (V1) and after 48 h (V2) through phone contact, and after 1 week from V0, on site (V3). The overall duration of the follow up was one week. An amelioration of 40% in WOMAC Physical Functional scores after 1 week of treatment was recorded, thus achieving the primary endpoint of 20%. Furthermore, a reduction of 29% in Physical Functional scores and of 28% in total WOMAC scores between V0-V2 was registered, together with a decrease of 39% between V0 and V3. The NRS scale showed a 29% and 37% reduction in pain between V0-V1 and V0-V2, respectively. Product safety was confirmed by the very low rate of adverse effects, non-device related, observed in only 2 patients out of 35, resolved spontaneously within 24-48 h. No safety concerns or risks associated with the use of the device were highlighted. There are few the studies on the topical use of HA-based gels for the treatment of knee problems. Compared to invasive intra-articular injections and oral pharmacological therapies used in cases of knee pain, the topical application of AI500® is non-invasive, safe, and appreciated by patients. Good results in terms of functional improvement and symptoms resolution were obtained in less than 1 week.

To assess the safety and effectiveness of high-density light-emitting diode (LED) irradiation therapy in patients with hand osteoarthritis (OA) and compare the pre- and post-intervention symptoms.

Twenty-three patients with hand OA underwent eight sessions of high-density LED irradiation therapy directed at the five most painful areas in the finger joints. Each session lasted for 18 minutes; and the sessions were conducted twice a week, for 4 weeks. We evaluated the degree of pain using the visual analogue scale, ring size, and passive range of motion (flexion+extension) for two most painful joints from the baseline to post-therapy (weeks 4 and 6).

High-density LED irradiation therapy significantly reduced the pain posttreatment compared with that observed at the baseline (p<0.001). Although improvements were observed in ring size and joint range of motion at 4 and 6 weeks, they were not statistically significant (p>0.05). No adverse events were observed.

We examined the safety and effectiveness of high-density LED irradiation therapy in reducing pain and hand swelling and improving joint mobility in patients with hand OA. These results suggest that high-density LED irradiation therapy has the potential to be an important strategy for managing hand OA.

Pain is the prime symptom of osteoarthritis (OA) that directly affects the quality of life. Protein kinase Cδ (PKCδ/Prkcd) plays a critical role in OA pathogenesis; however, its significance in OA-related pain is not entirely understood. The present study investigated the functional role of PKCδ in OA pain sensation. OA was surgically induced in control (Prkcdfl/fl), global- (Prkcdfl/fl; ROSACreERT2), and sensory neuron-specific conditional knockout (cKO) mice (Prkcdfl/fl; NaV1.8/Scn10aCreERT2) followed by comprehensive analysis of longitudinal behavioral pain, histopathology and immunofluorescence studies. GlobalPrkcd cKO mice prevented cartilage deterioration by inhibiting matrix metalloproteinase-13 (MMP13) in joint tissues but significantly increased OA pain. Sensory neuron-specificdeletion of Prkcd in mice did not protect cartilage from degeneration but worsened OA-associated pain. Exacerbated pain sensitivity observed in global- and sensory neuron-specific cKO of Prkcd was corroborated with markedly increased specific pain mediators in knee synovium and dorsal root ganglia (DRG). These specific pain markers include nerve growth factor (NGF) and vascular endothelial growth factor (VEGF), and their cognate receptors, including tropomyosin receptor kinase A (TrkA) and vascular endothelial growth factor receptor-1 (VEGFR1). The increased levels of NGF/TrkA and VEGF/VEGFR1 were comparable in both global- and sensory neuron-specific cKO groups. These data suggest that the absence of Prkcd gene expression in the sensory neurons is strongly associated with OA hyperalgesia independent of cartilage protection. Thus, inhibition of PKCδ may be beneficial for cartilage homeostasis but could aggravate OA-related pain symptoms.

Chemotherapy-induced neuropathic pain (CIPN) is a common side effect of antitumor chemotherapeutic agents. It describes a pathological state of pain related to the cumulative dosage of the drug, significantly limiting the efficacy of antitumor treatment. Sofas strategies alleviating CIPN still lack. Calcitonin gene-related peptide (CGRP) is a neuropeptide involved in many pathologic pains. In this study, we explored the effects of CGRP blocking on CIPN and potential mechanisms. Total dose of 20.7 mg/kg cisplatin was used to establish a CIPN mouse model. Mechanical and thermal hypersensitivity was measured using von Frey hairs and tail flick test. Western blot and immunofluorescence were utilized to evaluate the levels of CGRP and activated astrocytes in mouse spinal cord, respectively. In addition, real-time quantitative PCR (RT-qPCR) was used to detect the level of inflammatory cytokines such as IL-6, IL-1β, and NLRP3 in vitro and in vivo. There are markedly increased CGRP expression and astrocyte activation in the spinal cord of mice following cisplatin treatment. Pretreatment with a monoclonal antibody targeting CGRP (ZR8 mAb) effectively reduced cisplatin-induced mechanical hypersensitivity and thermal nociceptive sensitization and attenuated neuroinflammation as marked by downregulated expression of IL-6, IL-1β, and NLRP3 in the mice spinal cord and spleen. Lastly, ZR8 mAb does not interfere with the antitumor effects of cisplatin in tumor-bearing mice. Our findings indicate that neutralizing CGRP with monoclonal antibody could effectively alleviate CIPN by attenuating neuroinflammation. CGRP is a promising therapeutic target for CIPN.

Quadriceps strength deficits are known for patients with knee osteoarthritis (OA), whereas findings on hamstrings are less clear. The Adaptive Force (AF) as a special neuromuscular function has never been investigated in OA before. The maximal adaptive holding capacity (max. isometric AF; AFisomax) has been considered to be especially vulnerable to disruptive stimuli (e.g., nociception). It was hypothesized that affected limbs of OA patients would show clear deficits in AFisomax.

AF parameters and the maximal voluntary isometric contraction (MVIC) of hamstrings were assessed bilaterally comparing 20 patients with knee OA (ART) vs. controls (CON). AF was measured by a pneumatically driven device. Participants were instructed to maintain a static position despite an increasing load of the device. After reaching AFisomax, the hamstrings merged into eccentric action whereby the force increased further to the maximum (AFmax). MVIC was recorded before and after AF trials. Mixed ANOVA was used to identify differences between and within ART and CON (comparing 1st and 2nd measured sides).

AFisomax and the torque development per degree of yielding were significantly lower only for the more affected side of ART vs. CON (p ≤ 0.001). The percentage difference of AFisomax amounted to - 40%. For the less affected side it was - 24% (p = 0.219). MVIC and AFmax were significantly lower for ART vs. CON for both sides (p ≤ 0.001). Differences of MVIC between ART vs. CON amounted to - 27% for the more, and - 30% for the less affected side; for AFmax it was - 34% and - 32%, respectively.

The results suggest that strength deficits of hamstrings are present in patients with knee OA possibly attributable to nociception, generally lower physical activity/relief of lower extremities or fear-avoidance. However, the more affected side of OA patients seems to show further specific impairments regarding neuromuscular control reflected by the significantly reduced adaptive holding capacity and torque development during adaptive eccentric action. It is assumed that those parameters could reflect possible inhibitory nociceptive effects more sensitive than maximal strengths as MVIC and AFmax. Their role should be further investigated to get more specific insights into these aspects of neuromuscular control in OA patients. The approach is relevant for diagnostics also in terms of severity and prevention.