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Osteoarthritis (OA) is a prevalent joint disorder and the most common form of arthritis, affecting approximately 500 million people worldwide, or about 7% of the global population. Its pathogenesis involves a complex interplay between metabolic dysfunction and gut microbiome (GM) alterations. This review explores the relationship between metabolic disorders—such as obesity, diabetes, and dyslipidemia—and OA, highlighting their shared risk factors, including aging, sedentary lifestyle, and dietary habits. We further explore the role of GM dysbiosis in OA, elucidating how systemic inflammation, oxidative stress, and immune dysregulation driven by metabolic dysfunction and altered microbial metabolites contribute to OA progression. Additionally, the concept of "leaky gut syndrome" is discussed, illustrating how compromised gut barrier function exacerbates systemic and local joint inflammation. Therapeutic strategies targeting metabolic dysfunction and GM composition, including lifestyle interventions, pharmacological and non-pharmacological factors, and microbiota-targeted therapies, are reviewed for their potential to mitigate OA progression. Future research directions emphasize the importance of identifying novel biomarkers for OA risk and treatment response, adopting personalized treatment approaches, and integrating multiomics data to enhance our understanding of the metabolic–GM–OA connection and advance precision medicine in OA management. [ABSTRACT FROM AUTHOR]

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Objectives ACPA-positive and ACPA-negative RA differ in underlying risk factors but have a similar clinical presentation at RA diagnosis. It is unknown what the ACPA-associated differences or similarities are during the symptomatic at-risk stage of RA, i.e. clinically suspect arthralgia (CSA). To deepen insights into these differences/similarities, we compared the course of symptoms/impairments and subclinical joint inflammation in the CSA phase during progression to inflammatory arthritis (IA) or to CSA resolution. Methods A total of 845 CSA patients were followed for a median of 24 months; 136 patients developed IA and an additional 355/505 patients had resolution of CSA according to rheumatologists. Patient burden (pain, morning stiffness, fatigue, functional disabilities, presenteeism) was assessed at baseline and 4, 12 and 24 months and at IA development. Subclinical joint inflammation in the hands and feet was assessed over time with 1.5T MRI. Linear and Poisson mixed models were used. Results In both ACPA-positive and ACPA-negative patients, patient burden increased towards IA development and decreased towards CSA resolution. However, patient burden was lower in ACPA-positive vs ACPA-negative disease at all timepoints. Conversely, subclinical joint inflammation tended to increase more rapidly during development of ACPA-positive IA [incidence rate ratio (IRR) 1.52 (95% CI 0.94, 2.47), P  = 0.089] and remained higher over time in ACPA-positive CSA patients achieving resolution compared with ACPA-negative patients [IRR 1.52 (95% CI 1.07, 2.15), P  = 0.018]. Although correlation coefficients between changes in patient burden and subclinical joint inflammation during progression to IA were weak, they were consistently higher in ACPA-positive than ACPA-negative disease, e.g. ρ = 0.29 vs 0.12 for functional disabilities. Conclusion During RA development and CSA resolution, ACPA-positive CSA patients have lower patient burden but more subclinical joint inflammation than ACPA-negative CSA patients. These data strengthen the notion that the development of ACPA-positive and ACPA-negative RA is pathophysiologically different and encourage further research on these differences. [ABSTRACT FROM AUTHOR]

Simple Summary: This manuscript reports on an outbreak of joint infections in an organic broiler breeder flock in Austria, associated with two types of bacteria: Staphylococcus aureus and Staphylococcus lentus. The clinical picture of the affected chickens included weakness, lethargy, and difficulty walking, with some birds succumbing to the infection. Detailed examinations revealed severe joint inflammation and damage. Laboratory analyses confirmed the presence of both bacteria, with tests showing resistance to many antibiotics. This study underscores the importance of recognising and understanding less common bacteria like S. lentus, which are not frequently reported but can seriously impact poultry health. The findings highlight the need for thorough bacterial identification in outbreaks to improve disease management and prevention strategies. Staphylococcus species are widespread in poultry environments and can cause various infections, often when the host's defences are compromised. This manuscript reports on a co-infection of chickens with Staphylococcus lentus and Staphylococcus aureus associated with an outbreak of arthritis, synovitis, and osteomyelitis in an organic broiler breeder flock in Austria. Clinically, the affected flock showed weakness, lethargy, lameness, and increased mortality. Post-mortem examinations identified purulent arthritis and femoral head necrosis. Bacteriological analysis using MALDI-TOF MS identified both S. aureus and S. lentus in the affected joints. Antibiotic resistance testing revealed significant resistance, particularly in S. lentus. Histological analysis showed severe inflammation and bacterial colonies in the joints. While S. aureus is a common pathogen in poultry, S. lentus is less frequently reported. This study emphasises the need for detailed bacterial characterisation in outbreaks to better understand the role of less common pathogens like S. lentus. Further research is necessary to elucidate the impact of S. lentus on poultry health and its role in causing arthritis and synovitis, highlighting the importance of comprehensive investigation in such outbreaks. [ABSTRACT FROM AUTHOR]

Introduction: The prevalence of hyperuricemia is on the rise in specific populations, and there are difficulties in maintaining medication adherence. This study aims to investigate the factors linked to drug adherence in individuals with hyperuricemia. Methods: This was a cross-sectional study, which was conducted in 2023 by recruiting respondents with hyperuricemia. The demographic data collected included age, gender, occupation, body height and weight, education, marital status and ethnicity. Furthermore, drug adherence was determined based on the response to the Morisky Medication Adherence Scale-8. Acceptance and knowledge were measured using questionnaires given to the participants. Multivariate logistic regression analysis was then used to obtain the determinants of drug adherence. Results: Among 524 respondents who participated in the study, 60.3% and 30.15% had moderate and high adherence to serum uric acid-lowering drugs, respectively. The results showed that older age had a strong association with lower adherence (p <.01), while high disease acceptance significantly predicted higher levels (p <.01). Knowledge about gout symptoms (p =.003; OR: 0.28 [95% CI: 0.12-0.65]), causal factors (p <.001; OR: 2.63 [95% CI: 1.48-4.65]) and uric acid-lowering alternatives (p <.001; OR: 8.17 [95% CI: 4.11-16.25]) also had a positive correlation with higher levels. Conclusion: Knowledge and acceptance had a significant correlation with drug adherence among individuals with hyperuricemia in Aceh Province, Indonesia. [ABSTRACT FROM AUTHOR]

Aims: Adenosine, lidocaine, and Mg2+ (ALM) therapy exerts differential immuno-inflammatory responses in males and females early after anterior cruciate ligament (ACL) reconstruction (ACLR). Our aim was to investigate sex-specific effects of ALM therapy on joint tissue repair and recovery 28 days after surgery. Methods: Male (n = 21) and female (n = 21) adult Sprague-Dawley rats were randomly divided into ALM or Saline control treatment groups. Three days after ACL rupture, animals underwent ACLR. An ALM or saline intravenous infusion was commenced prior to skin incision, and continued for one hour. An intra-articular bolus of ALM or saline was also administered prior to skin closure. Animals were monitored to 28 days, and joint function, pain, inflammatory markers, histopathology, and tissue repair markers were assessed. Results: Despite comparable knee function, ALM-treated males had reduced systemic inflammation, synovial fluid angiogenic and pro-inflammatory mediators, synovitis, and fat pad fibrotic changes, compared to controls. Within the ACL graft, ALM-treated males had increased expression of tissue repair markers, decreased inflammation, increased collagen organization, and improved graft-bone healing. In contrast to males, females had no evidence of persistent systemic inflammation. Compared to controls, ALM-treated females had improved knee extension, gait biomechanics, and elevated synovial macrophage inflammatory protein-1 alpha (MIP-1α). Within the ACL graft, ALM-treated females had decreased inflammation, increased collagen organization, and improved graft-bone healing. In articular cartilage of ALM-treated animals, matrix metalloproteinase (MMP)-13 expression was blunted in males, while in females repair markers were increased. Conclusion: At 28 days, ALM therapy reduces inflammation, augments tissue repair patterns, and improves joint function in a sex-specific manner. The study supports transition to human safety trials. Cite this article: Bone Joint Res 2024;13(6):279–293.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and cartilage/bone destruction with systemic comorbidities. Despite advances in understanding the aetiology of RA and novel biologic drugs, a substantial number of individuals with RA remain intolerant or resistant to these therapies. In this context, mesenchymal stem/stromal cell (MSC)-based therapy has emerged as an innovative therapeutic alternative to address unresolved treatment issues for patients with RA thanks to the immunomodulatory properties of these cells. The majority of preclinical studies in MSC-based therapy have been conducted using the well-known collagen-induced arthritis (CIA) mouse model however due to its low incidence, the mouse strain restriction and the prolonged induction phase of collagen-induced arthritis, alternative experimental models of RA have been developed such as K/BxN serum transfer-induced arthritis (STIA), which mimics many of human RA features. In this study, we evaluate whether the K/BxN STIA model could be used as an alternative model to study the immunomodulatory potential of MSC-based therapy. Unexpectedly, our data suggest that adiposederived MSC-based therapy is unsuitable for modulating the progression of K/BxN serum-transfer arthritis in mice despite the various experimental parameters tested. Based on the differences in the immune status and monocytic/macrophage balance among the different arthritic models, these results could help to identify the cellular targets of the MSCs and, most importantly to predict the RA patients that will respond positively to MSC-based therapy. [ABSTRACT FROM AUTHOR]

Abstract Background The vasoactive neuropeptide calcitonin gene-related peptide alpha (αCGRP) enhances nociception in primary knee osteoarthritis (OA) and has been shown to disrupt cartilage and joint integrity in experimental rheumatoid arthritis (RA). Little is known about how αCGRP may alter articular structures in primary OA. We investigated whether αCGRP modulates local inflammation and concomitant cartilage and bone changes in a murine model of age-dependent OA. Methods Sixteen- to 18-month-old αCGRP-deficient mice (αCGRP−/− aged) were compared to, first, age-matched wild type (WTaged) and, second, young 4- to 5-month-old non-OA αCGRP-deficient (αCGRP−/− CTRL) and non-OA WT animals (WTCTRL). αCGRP levels were measured in serum. Knee and hip joint inflammation, cartilage degradation, and bone alterations were assessed by histology (OARSI histopathological grading score), gene expression analysis, and µ-computed tomography. Results WTaged mice exhibited elevated αCGRP serum levels compared to young WTCTRL animals. Marked signs of OA-induced cartilage destruction were seen in WTaged animals, while αCGRP−/− aged mice were mostly protected from this effect. Age-dependent OA was accompanied by an increased gene expression of pro-inflammatory Tnfa, Il1b, and Il6 and catabolic Mmp13, Adamts5, Ctsk, Tnfs11 (Rankl), and Cxcl12/Cxcr4 in WTaged but not in αCGRP−/− aged mice. αCGRP-deficiency however further aggravated subchondral bone sclerosis of the medial tibial plateau and accelerated bone loss in the epi- and metaphyseal trabecular tibial bone in age-dependent OA. Conclusions Similar to its function in experimental RA, αCGRP exerts a dual pro-inflammatory and bone-protective function in murine primary OA. Although anti-CGRP treatment was previously not successful in reducing pain in OA clinically, these data underline a crucial pathophysiological role of αCGRP in age-related OA.

AbstractContext: Gout is a chronic disease that imposes a huge financial and health burden on patients, which might diminish quality of life. Qin Jiao, a perennial herb found in northwestern China and Japan, is commonly used for treating various ailments.Objective: This study investigates the effects of Qin Jiao on gout and joint inflammation and elucidates its potential mechanism for gouty arthritis.Materials and methods: Study 1, a literature review was conducted using PubMed, Web of Science, and CNKI to assess the applications of Qin Jiao in arthritis treatment. Study 2 was performed to discover the component targets and gouty disease targets via TCMSP, OMIM, GeneCards and DRUGBANK, and network pharmacology analysis. Study 3, male Sprague-Dawley (SD) rats were divided into normal, model, colchicine, Qin Jiao low-dose (QJL), and Qin Jiao high-dose group (QJH), oral gavage for 40 d. Serum, synovial fluid, and synovial membrane tissue were collected to measure the expression levels of IL-1β, IL-6, and STAT3.Results: The research also identified potential targets and pharmacological pathways of Qin Jiao for gout treatment. In vivo study demonstrated Qin Jiao can reduce IL-1β levels in serum and ankle flushing fluid. ELISA analysis confirmed that Qin Jiao significantly reduces the protein expression of IL-6 and STAT3.Discussion and conclusion: Qin Jiao exerts anti-inflammatory effects on gouty arthritis by modulating the IL-6/STAT3 pathway. This study provides a biological basis for the use of Qin Jiao in treating arthritis-related diseases and offers experimental evidence for potential future drug development.

Osteoarthritis (OA) is a prevalent joint disorder and the most common form of arthritis, affecting approximately 500 million people worldwide, or about 7% of the global population. Its pathogenesis involves a complex interplay between metabolic dysfunction and gut microbiome (GM) alterations. This review explores the relationship between metabolic disorders—such as obesity, diabetes, and dyslipidemia—and OA, highlighting their shared risk factors, including aging, sedentary lifestyle, and dietary habits. We further explore the role of GM dysbiosis in OA, elucidating how systemic inflammation, oxidative stress, and immune dysregulation driven by metabolic dysfunction and altered microbial metabolites contribute to OA progression. Additionally, the concept of “leaky gut syndrome” is discussed, illustrating how compromised gut barrier function exacerbates systemic and local joint inflammation. Therapeutic strategies targeting metabolic dysfunction and GM composition, including lifestyle interventions, pharmacological and non-pharmacological factors, and microbiota-targeted therapies, are reviewed for their potential to mitigate OA progression. Future research directions emphasize the importance of identifying novel biomarkers for OA risk and treatment response, adopting personalized treatment approaches, and integrating multiomics data to enhance our understanding of the metabolic–GM–OA connection and advance precision medicine in OA management.

Secretome derived from mesenchymal stem cells (MSCs) have profound effects on tissue regeneration, which could become the basis of future MSCs therapies. Hypoxia, as the physiologic environment of MSCs, has great potential to enhance MSCs paracrine therapeutic effect. In our study, the paracrine effects of secretome derived from MSCs preconditioned in normoxia and hypoxia was compared through both in vitro functional assays and an in vivo rat osteochondral defect model. Specifically, the paracrine effect of total EVs were compared to that of soluble factors to characterize the predominant active components in the hypoxic secretome. We demonstrated that hypoxia conditioned medium, as well as the corresponding EVs, at a relatively low dosage, were efficient in promoting the repair of critical-sized osteochondral defects and mitigated the joint inflammation in a rat osteochondral defect model, relative to their normoxia counterpart. In vitro functional test shows enhancement through chondrocyte proliferation, migration, and matrix deposition, while inhibit IL-1β-induced chondrocytes senescence, inflammation, matrix degradation, and pro-inflammatory macrophage activity. Multiple functional proteins, as well as a change in EVs’ size profile, with enrichment of specific EV-miRNAs were detected with hypoxia preconditioning, implicating complex molecular pathways involved in hypoxia pre-conditioned MSCs secretome generated cartilage regeneration.

Context: Gout is a chronic disease that imposes a huge financial and health burden on patients, which might diminish quality of life. Qin Jiao, a perennial herb found in northwestern China and Japan, is commonly used for treating various ailments. Objective: This study investigates the effects of Qin Jiao on gout and joint inflammation and elucidates its potential mechanism for gouty arthritis. Materials and methods: Study 1, a literature review was conducted using PubMed, Web of Science, and CNKI to assess the applications of Qin Jiao in arthritis treatment. Study 2 was performed to discover the component targets and gouty disease targets via TCMSP, OMIM, GeneCards and DRUGBANK, and network pharmacology analysis. Study 3, male Sprague-Dawley (SD) rats were divided into normal, model, colchicine, Qin Jiao low-dose (QJL), and Qin Jiao high-dose group (QJH), oral gavage for 40 d. Serum, synovial fluid, and synovial membrane tissue were collected to measure the expression levels of IL-1β, IL-6, and STAT3. Results: The research also identified potential targets and pharmacological pathways of Qin Jiao for gout treatment. In vivo study demonstrated Qin Jiao can reduce IL-1β levels in serum and ankle flushing fluid. ELISA analysis confirmed that Qin Jiao significantly reduces the protein expression of IL-6 and STAT3. Discussion and conclusion: Qin Jiao exerts anti-inflammatory effects on gouty arthritis by modulating the IL-6/STAT3 pathway. This study provides a biological basis for the use of Qin Jiao in treating arthritis-related diseases and offers experimental evidence for potential future drug development. [ABSTRACT FROM AUTHOR]

Abstract Background Disruption of glucocorticoid (GC) signaling in osteoblasts results in a marked attenuation of acute antibody-induced arthritis. The role of endogenous GCs in chronic inflammatory arthritis is however not fully understood. Here, we investigated the impact of endogenous GC signaling in osteoblasts on inflammation and bone integrity under chronic inflammatory arthritis by inactivating osteoblastic GC signaling in a long-term K/BxN serum transfer-induced induced arthritis (STIA) model. Methods Intracellular GC signaling in osteoblasts was disrupted by transgenic (tg) overexpression of 11beta-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). Inflammatory arthritis was induced in 5-week-old male tg mice and their wild type (WT) littermates by intraperitoneal (i.p.) injection of K/BxN serum while controls (CTRLs) received phosphate-buffered saline (PBS). In a first cohort, K/BxN STIA was allowed to abate until the endpoint of 42 days (STIA). To mimic rheumatic flares, a second cohort was additionally injected on days 14 and 28 with K/BxN serum (STIA boost). Arthritis severity was assessed daily by clinical scoring and ankle size measurements. Ankle joints were assessed histopathologically. Systemic effects of inflammation on long bone metabolism were analyzed in proximal tibiae by micro-computed tomography (μCT) and histomorphometry. Results Acute arthritis developed in both tg and WT mice (STIA and STIA boost) and peaked around day 8. While WT STIA and tg STIA mice showed a steady decline of inflammation until day 42, WT STIA boost and tg STIA boost mice exhibited an arthritic phenotype over a period of 42 days. Clinical arthritis severity did not differ significantly between WT and tg mice, neither in the STIA nor in the STIA boost cohorts. Correspondingly, histological indices of inflammation, cartilage damage, and bone erosion showed no significant difference between WT and tg mice on day 42. Histomorphometry revealed an increased bone turnover in tg CTRL and tg STIA boost compared to WT CTRL and WT STIA boost animals, respectively. Conclusions In contrast to the previously reported modulating effects of endogenous GC signaling in osteoblasts during acute K/BxN STIA, this effect seems to perish during the chronic inflammatory and resolution phase. These findings indicate that endogenous GC signaling in osteoblasts may mainly be relevant during acute and subacute inflammatory processes.

Rheumatoid arthritis (RA) affects about 1% of the world's population and can lead to loss of joint function, reduced mobility, and permanent damage to cartilage and bone. Treatment options for RA primarily include disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, but the development of new drugs has complicated treatment decisions. Weighing treatment options for patients with RA largely depends on three major factors: efficacy, adverse reaction profile, and cost. A review of the literature supports methotrexate monotherapy as the current bestpractice model for treating RA, compared with combination therapy of methotrexate and/or other DMARDs. [ABSTRACT FROM AUTHOR]

PurposeTo assess the capability of in vivo positron emission tomography (PET) using 18 F-fluorodeoxyglucose (18 F-FDG) to quantify changes in inflammatory activity in response to tofacitinib, a Janus kinase (JAK) inhibitor, over a timeframe of a few hours to few days in a preclinical model of rheumatoid arthritis (RA).MethodsTwenty-four mice with collagen-induced arthritis in the following groups were assessed: Group 1, where the changes in PET measures for the extremity joints were evaluated at the peak and trough plasma drug levels after administration of a single dose of tofacitinib (4 hours apart); Group 2, where joint PET measures were assessed before treatment and after 6 days of administration of a daily dose of tofacitinib; and group 3 (controls), where joint PET measures were derived from the same mice, 6 days apart.ResultsAt about peak plasma levels of the drug after a single tofacitinib administration, there was a reduction in PET measures compared to pretreatment values, suggesting decreased inflammatory activity. These measures were equivalent to those obtained after 6 days of daily dosing by tofacitinib. However, PET measures at trough plasma levels of the drug from tofacitinib administration were significantly higher than those at peak plasma drug levels and equivalent to pretreatment measures. There were insignificant changes in PET measures for the control animals.Conclusion18 F-FDG PET can detect changes in inflammatory activity occurring in response to the JAK inhibitor tofacitinib: (a) during peak and trough plasma drug levels, that is within mere hours of treatment; and (b) over a span of days.

The inflammasome AIM2 regulates multiple aspects of innate immune functions and serves as a critical mediator of inflammatory responses. AIM2 inflammasome activation leads to the production of pro-inflammatory cytokines, IL-1β and IL-18 and participates triggering a pyroptosis response needed to counteract excessive cell proliferation. In addition, AIM2 expression and activation is wide regulated since alteration in its activity may derived in pathological consequences. Consequently, deregulated AIM2 activation contributes to the pathogenic processes of various inflammatory diseases. In this review, we will discuss the activation and function of AIM2 inflammasome, as well as its contribution in rheumatoid arthritis and systemic lupus erythematous pathology. Finally, we highlight the participation of the AIM2-inflammasome at the level of joint in rheumatoid arthritis and at kidney in systemic lupus erythematous. The development of therapeutic strategies based on modulation of AIM2-inflammasome activity should have a tissue-specific focus.

Background: Rheumatoid arthritis (RA) joint inflammation severely affects joint function and quality of life in patients and leads to joint deformities and limb disability. The non-steroidal anti-inflammatory drugs used in the treatment of RA do not fully control the progression of joint inflammation and bone destruction and have notable adverse reactions. Traditional Chinese medicine formula JuanBiQiangGu Granules (JBQG) are commonly used for the treatment of RA inflammation and delay of bone destruction, but has not been evaluated through high-quality clinical studies. There is a pressing need for well-designed, randomized, parallel, controlled clinical studies to evaluate the exact effect of JBQG on RA joint inflammation and improvement of patient quality of life. Methods: This is a randomized, parallel, controlled clinical study in which 144 patients with rheumatoid arthritis who met the inclusion criteria were randomly assigned to 2 groups in a 1:1 ratio. The JBQG group received methotrexate 7.5mg qw and JBQG granules 8mg tid, while theMTX group receivedmethotrexate 7.5mg qw. The endpoint was 12weeks after treatment. Relevant indices at baseline, 4weeks, 8 weeks, and 12weeks after treatment were observed and recorded, and DAS28-ESR, HAQ-DI, and Sharp scores were recorded for each patient. Blood samples were collected to test forCRP, ESR, TNF-α, IL-1β, IL-6, IL-17, and INF-γ, and adverse reactions and liver and kidney function (AST, ALT, Cr, BUN)were recorded for safety assessment. After 12weeks of treatment, the effect of JBQG granules on disease activity, improvement in bone damage, and patient quality of life scores and safety in RA patients were evaluated. Results: A total of 144 subjects completed treatment (71 in the JBQG group and 73 in the MTX group) and were included in the analysis. At baseline, there were no significant differences between the groups in terms of the observed indicators (p > 0.05). After treatment, 76.06% of patients in the JBQG group had DAS28-ESR Results: A total of 144 subjects completed treatment (71 in the JBQG group and 73 in the MTX group) and were included in the analysis. At baseline, there were no significant differences between the groups in terms of the observed indicators (p > 0.05). After treatment, 76.06% of patients in the JBQG group had DAS28-ESR levels below or equal to Low, including 45.07% in Remission and 5.63% in High, compared to 53.1% in theMTX group below or equal to Low, 12.33% in Remission, and 17.81% in High. CRP was significantly reduced (8.54 ± 5.87 vs. 11.86 ± 7.92, p < 0.05, p = 0.005), ESR was significantly reduced (15.1 ± 6.11 vs. 21.96 ± 9.19, p < 0.0001), TNF-a was significantly reduced (1.44 ± 0.83 vs. 1.85 ± 1.07, p < 0.05, p = 0.011), IL-17 was significantly reduced (0.53 ± 0.33 vs. 0.71 ± 0.38, p < 0.05, p = 0.004), and INF-γ was significantly reduced (3.2 ± 1.51 vs. 3.89 ± 1.77, p < 0.05, p = 0.014). The median (IQR) OPG in the JBQG group was 2.54 (2.21-3.01), significantly higher than in the MTX group 2.06 (1.81-2.32), p < 0.0001), and the median (IQR) β-CTX in the JBQG group was 0.4 (0.32-0.43), significantly lower than in the MTX group 0.55 (0.47-0.67), p < 0.0001). The median (IQR) VSA scores were 2 (1-3), a decrease from3 (2-4) in theMTX group (p < 0.0001). The median (IQR) Sharp scores were 1 (1-2), a decrease from 2 (1-2) in the MTX group, but the difference was not statistically significant (p > 0.05, p = 0.28). The median (IQR) HAQ-DI scores were 11 (8-16), significantly lower than in the MTX group 26 (16-30) (p < 0.0001). The median (IQR) AST in the JBQG group was 16 (12-20), with a significant difference compared to the MTX group 19 (13-25) (p < 0.01, p=0.004); themedian (IQR) ALT in the JBQGgroupwas 14 (10-18), with a significant difference compared to the MTX group 16 (11-22.5) (p < 0.05, p = 0.015). There were no statistically significant differences in Cr or BUN (p > 0.05). Conclusion: JuanBiQiangGu Granules can be used to treat patients with rheumatoid arthritis, alleviate joint inflammation, reduce the incidence of adverse reactions to methotrexate, and has good safety. [ABSTRACT FROM AUTHOR]

Background: Procalcitonin (PCT) is applied as a sensitive biomarker to exclude bacterial infections in patients with rheumatoid arthritis (RA) flare-ups. Beyond its diagnostic value, little is known about the pathophysiological role of PCT in RA. Methods: Collagen antibody-induced arthritis (CAIA) was induced in Calca-deficient mice (Calca−/−), lacking PCT (n = 15), and wild-type (WT) mice (n = 13), while control (CTRL) animals (n = 8 for each genotype) received phosphate-buffered saline. Arthritis severity and grip strength were assessed daily for 10 or 48 days. Articular inflammation, cartilage degradation, and bone lesions were assessed by histology, gene expression analysis, and µ-computed tomography. Results: Serum PCT levels and intra-articular PCT expression increased following CAIA induction. While WT animals developed a full arthritic phenotype, Calca-deficient mice were protected from clinical and histological signs of arthritis and grip strength was preserved. Cartilage turnover markers and Tnfa were exclusively elevated in WT mice. Calca-deficient animals expressed increased levels of Il1b. Decreased bone surface and increased subchondral bone porosity were observed in WT mice, while Calca-deficiency preserved bone integrity. Conclusion: The inactivation of Calca and thereby PCT provided full protection from joint inflammation and arthritic bone loss in mice exposed to CAIA. Together with our previous findings on the pathophysiological function of Calca-derived peptides, these data indicate an independent pro-inflammatory role of PCT in RA. [ABSTRACT FROM AUTHOR]

Simple Summary: Undenatured type II collagen and Boswellia serrata are feed supplements that have been used for years in the multimodal management of osteoarthritis (OA), with the aim of maintaining articular cartilage and reducing the inflammatory state. The objective of this review is to analyse how the administration of undenatured type II collagen and Boswellia serrata or both combined in the same product influences the management of OA and helps support joint health and mobility. Twenty-six articles were selected, which were carefully analysed. It was observed, based on different methods, that the use of these two feed supplements is a valid option for the long-term multimodal management of OA, improves the general condition, appetite and mobility, and reduces the degree of lameness. Its use before intense exercise is associated with greater activity and less response from inflammatory biomarkers. In the multimodal management of osteoarthritis (OA) in recent decades, the use of feed supplements to maintain joint cartilage has been advocated. The aim of this scoping review is to present the results found in the veterinary literature on the use of undenatured type II collagen and Boswellia serrata in dogs, specifically its use in dogs with clinical signs of OA, healthy dogs after intense exercise or dogs with diseases that predispose the individual to OA. For this purpose, a literature review was carried out using the electronic databases PubMed, Web of Science and Google Scholar, from which a total of 26 records were included in this review: fourteen evaluating undenatured type II collagen, ten evaluating Boswellia serrata and two evaluating the combination of undenatured type II collagen and Boswellia serrata. The review of the records showed that undenatured type II collagen decreases the clinical signs associated with OA, improving the general clinical state with a reduction in the degree of lameness and increase in physical activity or mobility. Evaluating the response to supplementation with Boswellia serrata alone is complicated due to the limited publication of studies and variations in the purity and compositions of the products used, but in general terms, its combination with other feed supplements produces benefits by relieving pain and reducing the clinical signs of OA in dogs. The combination of both in the same product provides results similar to those obtained in undenatured type II collagen studies. In conclusion, undenatured type II collagen and Boswellia serrata are considered a valid option for the multimodal approach to the management of OA and for improving activity during intense exercise, but more studies are needed to conclude whether or not it prevents OA in dogs. [ABSTRACT FROM AUTHOR]

Introduction: Peptidylarginine deiminases (PADs) mediate citrullination, an irreversible posttranslational modification that converts arginine to citrulline residues in proteins. Rheumatoid arthritis (RA) is characterized by unique autoantibodies that recognize citrullinated peptides, which are highly specific for this disease. However, the mechanism preceding the anti-citrulline response remains largely unclear. PAD enzymes are known to fuel the autoimmune response by generating autoreactive epitopes, and sustain local synovial inflammation through neutrophil extracellular trap formation. Therefore, detecting endogenous PAD activity is important to understand the pathogenesis of arthritis. Methods: In this study, we improved a fluorescent in vitro assay to enable endogenous PAD activity characterization in complex samples. We combine the use of an in-house synthetic, arginine-rich substrate and a negatively charged dye molecule to visualize enzyme activity. Results: This pioneering PAD assay allowed profiling of active citrullination in leukocytes and in local and systemic samples of an arthritis cohort. Our results reveal that RA and juvenile idiopathic arthritis (JIA) synovial fluids display similar levels of PAD activity. In contrast, citrullination was limited in joints of patients suffering from gout or Lyme’s disease. Interestingly, in blood, a higher level of extracellular citrullination was only found in anti-CCP-positive RA patients. Discussion: Our finding suggests that enhanced synovial PAD activity drives the loss in tolerance towards citrullinated proteins and that systemic citrullination may indicate the risk for developing citrulline-specific autoimmunity [ABSTRACT FROM AUTHOR]

Background: Rarely, chronic tophaceous gout can result in lumbar spinal stenosis and neural compression. Case Description: A 67-year-old male presented with the radiographic and magnetic resonance findings of gout involving and causing compression of the lumbar spine that responded to surgical decompression. Conclusion: It is difficult to diagnose lumbar spinal stenosis secondary to tophaceous gout. Notably, the treatment, based on the clinical presentation, may include both medication and surgical decompression. [ABSTRACT FROM AUTHOR]

Objective: Rheumatoid arthritis (RA) is an autoimmune disease where sera and synovial fluid (SF) of suffering patients contain immune complexes formed from autoantibodies to several proteins. SF from humans with joint diseases was examined for the presence of some inflammatory parameters and autoantibodies. Materials and Methods: Antibodies in their free and complex forms were assayed by indirect ELISA. The immunoprecipitation technique was used to evaluate total IgG and IgM and complement. Results: The results showed that most RA SF was anti-ASLO negative, but they were CRP positive. Levels of complement components (C3 and C4) were highest in the group of mono-/oligo-arthritis and lowest in RA. The results showed that xanthine oxidase (XO) presence and activity were important in SF of RA patients. Moreover, free and complex anti-XO antibodies were detected in all SF with different titers throughout the groups of patients where IgG was lower than IgM. Conclusion: The studied parameters of inflammation and auto-antibodies especially against XO could serve as an evaluation of the severity of joint inflammation and in RA pathogenesis understanding. [ABSTRACT FROM AUTHOR]

The inflammasome AIM2 regulates multiple aspects of innate immune functions and serves as a critical mediator of inflammatory responses. AIM2 inflammasome activation leads to the production of pro-inflammatory cytokines, IL-1β and IL-18 and participates triggering a pyroptosis response needed to counteract excessive cell proliferation. In addition, AIM2 expression and activation is wide regulated since alteration in its activity may derived in pathological consequences. Consequently, deregulated AIM2 activation contributes to the pathogenic processes of various inflammatory diseases. In this review, we will discuss the activation and function of AIM2 inflammasome, as well as its contribution in rheumatoid arthritis and systemic lupus erythematous pathology. Finally, we highlight the participation of the AIM2-inflammasome at the level of joint in rheumatoid arthritis and at kidney in systemic lupus erythematous. The development of therapeutic strategies based on modulation of AIM2-inflammasome activity should have a tissue-specific focus. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and cartilage/bone destruction with systemic comorbidities. Despite advances in understanding the aetiology of RA and novel biologic drugs, a substantial number of individuals with RA remain intolerant or resistant to these therapies. In this context, mesenchymal stem/stromal cell (MSC)- based therapy has emerged as an innovative therapeutic alternative to address unresolved treatment issues for patients with RA thanks to the immunomodulatory properties of these cells. The majority of preclinical studies in MSC-based therapy have been conducted using the well-known collagen-induced arthritis (CIA) mouse model however due to its low incidence, the mouse strain restriction and the prolonged induction phase of collagen-induced arthritis, alternative experimental models of RA have been developed such as K/BxN serum transfer-induced arthritis (STIA), which mimics many of human RA features. In this study, we evaluate whether the K/BxN STIA model could be used as an alternative model to study the immunomodulatory potential of MSC-based therapy. Unexpectedly, our data suggest that adiposederived MSC-based therapy is unsuitable for modulating the progression of K/ BxN serum-transfer arthritis in mice despite the various experimental parameters tested. Based on the differences in the immune status and monocytic/macrophage balance among the different arthritic models, these results could help to identify the cellular targets of the MSCs and, most importantly to predict the RA patients that will respond positively to MSCbased therapy. [ABSTRACT FROM AUTHOR]

Abstract Background Galactosialidosis (GS) is a rare inherited lysosomal storage disorder (LSD) which is characterized by a defect in the lysosomal glycoprotein catabolism. We report, for the first time, the case of a child affected by GS presenting with recurrent episodes of extensive joint inflammation in both knee joints. The aim of this case-report is to describe the clinical presentation as well as the laboratory, radiologic and microscopic features of this unique presentation of GS. Furthermore, we explore inflammatory mechanisms potentially responsible for the origination of the arthritic joint pathology observed in our patient. Case presentation We describe the rare case of a 12-year-old boy diagnosed with GS (late infantile form) who presented with multiple episodes of inflammatory arthritis involving both knees; no other joints were suspected for joint inflammation. Laboratory results did not indicate an autoimmune disorder. Synovial fluid tested negative for any bacterial infection and ruled out a malignancy and crystal-induced arthritis. Microscopic examination of the synovial tissue revealed numerous foamy macrophages with extensive vacuolization, consistent with the previous diagnosis of GS. Treatment consisted of aspiration of excessive joint fluid and subsequent intra-articular injection of triamcinolonhexacetonide with excellent but transient result. Given the evidence of storage products within macrophages of the inflamed synovial tissue and the absence of other etiological clues, GS itself was considered as the primary cause for the relapsing inflammatory joint pathology. According to the restricted data on articular manifestations in GS, to date, GS cannot be linked directly to joint inflammation. Nevertheless, in several other LSDs, the accumulation of storage material has been associated with numerous osteoimmunological changes that might play a role in the pathophysiology of arthritic processes. Conclusions We hypothesize that the articular build-up of GS storage products triggered systemic as well as local inflammatory processes, resulting in the extensive inflammatory joint pathology as observed in our patient. Future identification of other patients with GS is required to corroborate the existence of an arthritic clinical phenotype of GS and to assess the underlying pathophysiology.

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation. Immune dysfunction is an essential mechanism in the pathogenesis of RA and directly linked to synovial inflammation and cartilage/bone destruction. Intermediate conductance Ca2+-activated K+ channel (KCa3.1) is considered a significant regulator of proliferation, differentiation, and migration of immune cells by mediating Ca2+ signal transduction. Earlier studies have demonstrated abnormal activation of KCa3.1 in the peripheral blood and articular synovium of RA patients. Moreover, knockout of KCa3.1 reduced the severity of synovial inflammation and cartilage damage to a significant extent in a mouse collagen antibody-induced arthritis (CAIA) model. Accumulating evidence implicates KCa3.1 as a potential therapeutic target for RA. Here, we provide an overview of the KCa3.1 channel and its pharmacological properties, discuss the significance of KCa3.1 in immune cells and feasibility as a drug target for modulating the immune balance, and highlight its emerging role in pathological progression of RA.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and cartilage/bone destruction with systemic comorbidities. Despite advances in understanding the aetiology of RA and novel biologic drugs, a substantial number of individuals with RA remain intolerant or resistant to these therapies. In this context, mesenchymal stem/stromal cell (MSC)-based therapy has emerged as an innovative therapeutic alternative to address unresolved treatment issues for patients with RA thanks to the immunomodulatory properties of these cells. The majority of preclinical studies in MSC-based therapy have been conducted using the well-known collagen-induced arthritis (CIA) mouse model however due to its low incidence, the mouse strain restriction and the prolonged induction phase of collagen-induced arthritis, alternative experimental models of RA have been developed such as K/BxN serum transfer-induced arthritis (STIA), which mimics many of human RA features. In this study, we evaluate whether the K/BxN STIA model could be used as an alternative model to study the immunomodulatory potential of MSC-based therapy. Unexpectedly, our data suggest that adipose-derived MSC-based therapy is unsuitable for modulating the progression of K/BxN serum-transfer arthritis in mice despite the various experimental parameters tested. Based on the differences in the immune status and monocytic/macrophage balance among the different arthritic models, these results could help to identify the cellular targets of the MSCs and, most importantly to predict the RA patients that will respond positively to MSC-based therapy.

Abstract Background Rheumatoid arthritis (RA) is a systemic chronic disease with synovial membrane, tendon and articular tissue inflammation. Current treatments of RA have many side effects and are quite expensive. Today, new treatments procedures and inexpensive herbal drugs are developed. Marham‐Mafasel is mainly made out of two traditional herbs (Arnebia euchroma and Martricaria chamomilla). Objective In this study, for the first time, the impact of Marham‐Mafasel on joint inflammation, histopathological changes and IL‐1β gene expression was evaluated in RA animal model. Methods The RA was induced by a single s.c. injection of 0.1 ml Freund's complete adjuvant into the left hind footpad. In continuous, 15 RA male Wistar rats were used in three groups: I: Control; II: Treatment I (Piroxicam) and III: Treatment II (Marham‐Mafasel). The volume of the hind paw was measured every day from 0 to 19 using water changed volume approach. The inflammation in the joint was evaluated using histopathology assay and gene expression of IL‐1β was evaluated with use of Real‐Time PCR. Results Hind paw swelling of Marham‐Mafasel at days 10th and 19th was reduced compared with the control group (p

Arthritis and prosthetic joint infections (PJIs) overall are associated with reduced quality of life and limited work capacity. Multiple, overlapping factors contribute to these conditions. Some investigations have suggested a dysbiotic association between the oral‐gut microbiome and pathogenesis of arthritis and PJIs. A better understanding of the role of the oral‐gut microbiota in arthritis and PJI pathophysiology can shed light into how its disequilibrium can discharge a pro‐inflammatory response, and impact the health of patients susceptible to arthritis or with established joint disease. A review of published in vivo and clinical data suggested that alterations in oral and gut microbiota can lead to a disturbance of immunoregulatory properties, and may be associated with joint infections and arthritis. This review brings new insights into the current status of the evidence on the potential molecules and inflammatory biomarkers disrupted by an oral‐gut microbial dysbiosis. Normal commensals and pathogenic oral and gut microflora homeostasis are important not only to prevent infections per se but also its potential progression. Further experiments, especially controlled clinical trials, are needed to ascertain how microbiome manipulation and other microbiota‐directed approaches can help control inflammation and effectively prevent and treat arthritic diseases. Additionally, studies on the effects of the long‐term oral diseases, such as chronic periodontitis, on arthritis and PJIs need to be conducted. [ABSTRACT FROM AUTHOR]

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The term inflammatory arthritis defines a family of diseases, including rheumatoid arthritis (RA), caused by an overactive immune system, and influenced by host aspects including sex, reproductive state, and stress. Prolactin (PRL) is a sexually dimorphic, reproductive, stress-related hormone long-linked to RA under the general assumption that it aggravates the disease. However, this conclusion remains controversial since PRL has both negative and positive outcomes in RA that may depend on the hormone circulating levels, synthesis by joint tissues, and complex interactions at the inflammatory milieu. The inflamed joint is rich in matrix metalloproteases that cleave PRL to vasoinhibin, a PRL fragment with proinflammatory effects and the ability to inhibit the hyperpermeability and growth of blood vessels. This review addresses this field with the idea that explanatory mechanisms lie within the PRL/vasoinhibin axis, an integrative framework influencing not only the levels of systemic and local PRL, but also the proteolytic conversion of PRL to vasoinhibin, as vasoinhibin itself has dual actions on joint inflammation. In this review, we discuss recent findings from mouse models suggesting the upregulation of endogenous vasoinhibin by the pro-inflammatory environment and showing dichotomous actions and signaling mechanisms of PRL and vasoinhibin on joint inflammation that are cell-specific and context-dependent. We hypothesize that these opposing actions work together to balance the inflammatory response and provide new insights for understanding the pathophysiology of RA and the development of new treatments. [ABSTRACT FROM AUTHOR]

Abstract Background Informative serum biomarkers for monitoring inflammatory activity and treatment responses in axial spondyloarthritis (axSpA) are lacking. We assessed whether Lipocalin 2 (LCN2) and Oncostatin M (OSM), both having roles in inflammation and bone remodeling, may accurately reflect chronic joint inflammation and treatment response in axSpA. Previous reports in animal models showed involvement of LCN2 and OSM in joint/gut inflammation. We asked whether they also play a role in human axSpA. Methods We analyzed a longitudinal observational axSpA cohort (286 patients) with yearly clinical assessments and concurrent measurements of serum LCN2 and OSM (1204 serum samples) for a mean of 4 years. Biomarker levels were correlated with MRI scoring and treatment response. Results Persistent and transient elevation of LCN2 and OSM were observed in axSpA patients. Persistent elevation of LCN2 or OSM, but not CRP, correlated with sacroiliac joint (SIJ) MRI SPARCC scores (Pearson’s correlation p = 0.0005 and 0.005 for LCN2 and OSM respectively), suggesting that LCN2/OSM outperforms CRP as reflective of SIJ inflammation. We observed both concordant and discordant patterns of LCN2 and OSM in relationship to back pain, the cardinal clinical symptom in axSpA. Twenty-six percent (73/286) of the patients remained both clinically and serologically active (CASA). Sixty percent (173/286) of the patients became clinically quiescent, with back pain resolved, but 53% (92/173) of them were serologically active (CQSA), indicating that pain control may not indicate control of joint inflammation, as reflected by positive MRI imaging of SIJ. With respect to treatment responses, transient elevation of LCN2 or OSM over time was predictive of better response to all treatments. Conclusion In axSpA, persistent LCN2 and/or OSM elevation reflects chronic SIJ inflammation and suboptimal treatment response. In our cohort, half of the currently deemed clinically quiescent patients with back pain resolved continued to demonstrate chronic joint inflammation. LCN2 and OSM profiling outperforms CRP as a predictive measure and provides an objective assessment of chronic local inflammation in axSpA patients.

The term inflammatory arthritis defines a family of diseases, including rheumatoid arthritis (RA), caused by an overactive immune system, and influenced by host aspects including sex, reproductive state, and stress. Prolactin (PRL) is a sexually dimorphic, reproductive, stress-related hormone long-linked to RA under the general assumption that it aggravates the disease. However, this conclusion remains controversial since PRL has both negative and positive outcomes in RA that may depend on the hormone circulating levels, synthesis by joint tissues, and complex interactions at the inflammatory milieu. The inflamed joint is rich in matrix metalloproteases that cleave PRL to vasoinhibin, a PRL fragment with proinflammatory effects and the ability to inhibit the hyperpermeability and growth of blood vessels. This review addresses this field with the idea that explanatory mechanisms lie within the PRL/vasoinhibin axis, an integrative framework influencing not only the levels of systemic and local PRL, but also the proteolytic conversion of PRL to vasoinhibin, as vasoinhibin itself has dual actions on joint inflammation. In this review, we discuss recent findings from mouse models suggesting the upregulation of endogenous vasoinhibin by the pro-inflammatory environment and showing dichotomous actions and signaling mechanisms of PRL and vasoinhibin on joint inflammation that are cell-specific and context-dependent. We hypothesize that these opposing actions work together to balance the inflammatory response and provide new insights for understanding the pathophysiology of RA and the development of new treatments.

BackgroundAllogenic mesenchymal stem cell (MSC) secretome is a novel intra-articular therapeutic that has shown promise in in vitro and small animal models and warrants further investigation.ObjectivesTo investigate if intra-articular allogenic MSC-secretome has anti-inflammatory effects using an equine model of joint inflammation.Study DesignRandomized positively and negatively controlled experimental study.MethodIn phase 1, joint inflammation was induced bilaterally in radiocarpal joints of eight horses by injecting 0.25 ng lipopolysaccharide (LPS). After 2 h, the secretome of INFy and TNFα stimulated allogeneic equine MSCs was injected in one randomly assigned joint, while the contralateral joint was injected with medium (negative control). Clinical parameters (composite welfare scores, joint effusion, joint circumference) were recorded, and synovial fluid samples were analyzed for biomarkers (total protein, WBCC; eicosanoid mediators, CCL2; TNFα; MMP; GAGs; C2C; CPII) at fixed post-injection hours (PIH 0, 8, 24, 72, and 168 h). The effects of time and treatment on clinical and synovial fluid parameters and the presence of time-treatment interactions were evaluated. For phase 2, allogeneic MSC-secretome vs. allogeneic equine MSCs (positive control) was tested using a similar methodology.ResultsIn phase 1, the joint circumference was significantly (p < 0.05) lower in the MSC-secretome treated group compared to the medium control group at PIH 24, and significantly higher peak synovial GAG values were noted at PIH 24 (p < 0.001). In phase 2, no significant differences were noted between the treatment effects of MSC-secretome and MSCs.Main LimitationsThis study is a controlled experimental study and therefore cannot fully reflect natural joint disease. In phase 2, two therapeutics are directly compared and there is no negative control.ConclusionsIn this model of joint inflammation, intra-articular MSC-secretome injection had some clinical anti-inflammatory effects. An effect on cartilage metabolism, evident as a rise in GAG levels was also noted, although it is unclear whether this could be considered a beneficial or detrimental effect. When directly comparing MSC-secretome to MSCs in this model results were comparable, indicating that MSC-secretome could be a viable off-the-shelf alternative to MSC treatment.

AbstractOsteoarthritis (OA) is the most common condition affecting human joints. Along with mechanical and genetic factors, low-grade inflammation is increasingly supported as a causal factor in the development of OA. Gut microbiota and intestinal permeability, via the disruption of tight junction competency, are proposed to explain a gut-joint axis through the interaction with the host immune system. Since previous studies and methods have underestimated the role of the gut-joint axis in OA and have only focussed on the characterisation of microbiota phenotypes, this systematic review aims to appraise the current evidence concerning the influence of gut permeability in the pathogenesis of OA. We propose that the tight junction disruption may be due to an increase in zonulin activity as already demonstrated for many other chronic inflammatory disorders. After years of unreliable quantification, one study optimised the methodology, showing a positive validated correlation between plasma lipopolysaccharide (LPS), obesity, joint inflammation, and OA severity. Chemokines show a prominent role in pain development. Our systematic review confirms preliminary evidence supporting a gut-joint axis in OA pathogenesis and progression. Being modifiable by several factors, the gut microbiota is a promising target for treatment. We propose a pathogenetic model in which dysbiosis is correlated to the bipartite graph of tight junctions and bacterially-produced products, aiming to direct future studies in the search of other bacterial products and tight junction disassembly regulators.KEY MESSAGESPrevious studies and methods have underestimated the impact of the gut-joint axis in osteoarthritis and have focussed on the characterisation of microbiota phenotypes rather than clear molecular mediators of disease.Gut dysbiosis is related to higher levels of bacterial toxins that elicit cartilage and synovium inflammatory pathways.Future research may benefit from focussing on both tight junctions and bacterially-produced products.

Joint inflammation results from soft-tissue injuries and cartilage damage. PRICE is the standard treatment approach for acute soft tissue injuries like ankle sprain. Electrical stimulation, application of orthotic braces, etc. is also effective for this. In a synergistic device all these components are combined and applied simultaneously. This device was developed for joint inflammation and tested for grade I & II acute ankle joint sprain. To test a synergistic – semirigid device, combining PRICE & electrical stimulation for acute ankle sprains of grades I & II for pain, range of motion and swelling is a case series was the objective. Device was developed using novel concept of synergistic applications of PRICE with electrical stimulation. The joint contour of ankle and specific biomechanical bony surface landmarks were considered. Ethical approval was taken from NTCC committee, AIPT. Recordings were taken from eight patients of acute ankle sprain with – in two days of injury, after getting ethical approval. Elevation to the ankle was provided by keeping the part over the pillow and data was recorded with the help of: 1.VAS scale for pain; 2. Measuring tape; 3. Goniometry. t-test was used to find out the significant difference pre and post the application of device. There was a significant reduction in pain (p = 0.006), edema (p = 0.011), dorsi-flexion (p = 0.015), and plantar flexion (p =0.008). The synegistic device has been effective for acute ankle inflammation - grade I & II ankle sprains in 5 sessions; sufficient for the return of function. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects the joints and is associated with excessive immune cell infiltration. However, the complex interactions between the immune cell populations in the RA synovium remain unknown. Here, we demonstrate that inflammatory macrophages in the synovium exacerbate neutrophil-driven joint damage in RA through ADP/P2Y1 signaling. We show that extracellular ADP (eADP) and its receptors are obviously increased in synovial tissues of RA patients as well as collagen-induced arthritis (CIA) mice, and eADP enhances neutrophil infiltration into joints through macrophages producing the chemokine CXCL2, aggravating disease development. Accordingly, the arthritis mouse model had more neutrophils in inflamed joints following ADP injection, whereas P2Y1 deficiency and pharmacologic inhibition restored arthritis severity to basal levels, suggesting a dominant role of ADP/P2Y1 signaling in RA pathology. Moreover, cellular activity of ADP/P2Y1-mediated CXCL2 production was dependent on the Gαq/Ca2+-NF-κB/NFAT pathway in macrophages. Overall, this study reveals a non-redundant role of eADP as a trigger in the pathogenesis of RA through neutrophil recruitment and disrupted tissue homeostasis and function. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA), a chronic auto-immune disease, is often result of persistent and misdirectional inflammation and cannot be effectually resolved by single-target selective drugs. Present study attempted to uncover anti-arthritic efficacy and governing molecular mechanism of BLFE and its phytoconstituents berberine and rutin, with focus on dysregulated oxi-inflammation and structural integrity during articular damage using Collagen II–CFA-induced RA mice model. NMR-based phytometabolomic analysis revealed presence of phenolics and alkaloids such as berberine and rutin. BLFE, rutin and berberine remarkably mitigated Collagen II–CFA-induced disease severity index, articular damage, immune cells influx and pannus formation. An effective decrease in levels of TNF-α, IL-6, IL-1β, IFN-γ, IL-13, IL-17, MMPs, RORγt, Ob-cadherin, Cox-2, iNOS and enhancement in IL-10, IL-4 and IL-5, BMP-6/7 was observed in BLFE, rutin and berberine treatments. Molecular mechanistic analysis demonstrated reduction in expression of p-STAT-1/3, p-PI3K, p-Akt, p-JNK, p-p38, p-IκB, p-NF-κB and β-catenin via BLFE, rutin and berberine. Furthermore, reduced activation of p-ERK and p-GSK3β and enhanced splenic Tregs was only noticed in BLFE and berberine. Thus, the signifying presence of these phytoconstituents could contribute to the above-mentioned findings. These findings imply that BLFE could be beneficial for assuaging deleterious aspects of RA mediated via perturbed inflammation. [ABSTRACT FROM AUTHOR]

Qian Bai,1 Jing Cao,2 Tieli Dong,1 Feng Tao3 1Department of Anesthesiology, The Second Affiliated Hospital of Zhengzhou University, Henan, People’s Republic of China; 2Department of Anatomy, School of Basic Medical Sciences, Zhengzhou University, Henan, People’s Republic of China; 3Department of Biomedical Sciences, Texas A&M University College of Dentistry, Dallas, Texas, USACorrespondence: Tieli DongThe Second Affiliated Hospital of Zhengzhou University, Henan, People’s Republic of ChinaEmail tlddtl@126.comFeng TaoTexas A&M University College of Dentistry, Dallas, Texas, USAEmail ftao81@tamu.eduBackground: Rheumatoid arthritis (RA) leads to pain through alteration of gene expression. Although gene expression alteration in knee cartilage or peripheral blood from RA patients has been identified using microarray, it remains unclear whether long non-coding RNA (lncRNA)-mediated gene regulation occurs in primary sensory neurons of dorsal root ganglia (DRG) during RA-like joint inflammation. In the present study, we aimed to analyze lncRNA and related mRNA profiles in the DRG in a knee joint inflammation rat model.Methods: Complete Freund’s adjuvant (CFA) was injected in the rat knee joint for preparing the joint inflammation model. A lncRNA-mRNA microarray of rat DRG was employed for transcriptome analysis. Functional roles of differentially expressed lncRNAs and their related mRNAs in the injured DRG were delineated by bioinformatic analysis.Results: We observed that expression levels of 9000 lncRNAs were altered on day 7 post-CFA, of which 45.17% were up-regulated and 54.83% were down-regulated. Specifically, 69 lncRNAs (42 up and 27 down) were significantly regulated. We also observed that expression levels of 13,744 mRNAs were altered on day 7 post-CFA, of which 49.67% were up-regulated and 50.33% were down-regulated. Specifically, 102 mRNAs (51 up and 51 down) were significantly regulated. Using quantitative real-time PCR, we verified the changes in differentially expressed lncRNAs in the injured DRG.Conclusion: These results suggest that microarray-based RNA sequencing can be used to identify altered lncRNAs and relevant mRNAs in the DRG of rats with knee joint inflammation.Keywords: joint inflammation, dorsal root ganglion, transcriptome analysis

Septic arthritis (SA) is a medical emergency. The most common etiological agents are bacteria, which activate the local immune response coordinated by cytokines; however, little is known about the cytokine profile in human SA. To determine the association of local and systemic cytokine profiles with the severity and prognosis of patients with SA. Patients with clinical and laboratory diagnosed SA were enrolled as well as a control group. Serum and synovial fluid (SF) samples were obtained for determining cytokines and glucose levels; SF samples were used for histological analysis. Osteochondral damage and general health status and quality of life (SF-36) were evaluated during recruitment day. WOMAC osteoarthritis index score and SF-36 questionnaire were used a year after recruitment day as a follow up. A systemic and local proinflammatory cytokine profile was found in patients compared to the control group (p <0.05). IL-6 was 28 and 525 times higher than controls in sera and SF, respectively (p < 0.0001). Systemic IL-6 correlated negatively with general mental health score (p = 0.0184) and was associated with a higher osteoarthritis index after one year follow-up in the patients (p = 0.0352). HMGB1 in SF was found higher in patients with SA (p <0.0001), and it was associated with osteochondral damage (p = 0.0042). TNF-α in SF correlated negatively with SF-36 questionnaire one year after patients' recruitment in role limitation score (p = 0.0318), body pain score (p = 0.0315), and general mental health score (p = 0.0197). Serum and SF cytokine signatures are associated with disease severity and prognosis in patients with SA. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is the most common condition affecting human joints. Along with mechanical and genetic factors, low-grade inflammation is increasingly supported as a causal factor in the development of OA. Gut microbiota and intestinal permeability, via the disruption of tight junction competency, are proposed to explain a gut-joint axis through the interaction with the host immune system. Since previous studies and methods have underestimated the role of the gut-joint axis in OA and have only focussed on the characterisation of microbiota phenotypes, this systematic review aims to appraise the current evidence concerning the influence of gut permeability in the pathogenesis of OA. We propose that the tight junction disruption may be due to an increase in zonulin activity as already demonstrated for many other chronic inflammatory disorders. After years of unreliable quantification, one study optimised the methodology, showing a positive validated correlation between plasma lipopolysaccharide (LPS), obesity, joint inflammation, and OA severity. Chemokines show a prominent role in pain development. Our systematic review confirms preliminary evidence supporting a gut-joint axis in OA pathogenesis and progression. Being modifiable by several factors, the gut microbiota is a promising target for treatment. We propose a pathogenetic model in which dysbiosis is correlated to the bipartite graph of tight junctions and bacterially-produced products, aiming to direct future studies in the search of other bacterial products and tight junction disassembly regulators. Previous studies and methods have underestimated the impact of the gut-joint axis in osteoarthritis and have focussed on the characterisation of microbiota phenotypes rather than clear molecular mediators of disease. Gut dysbiosis is related to higher levels of bacterial toxins that elicit cartilage and synovium inflammatory pathways. Future research may benefit from focussing on both tight junctions and bacterially-produced products. [ABSTRACT FROM AUTHOR]

Shalini Srivastava,1 Jayesh A Chaudhary,2 Robert N Girandola3 1Department of Clinical Development, Enovate Biolife, Mumbai, Maharashtra, India; 2Vedic Lifesciences, Mumbai, Maharashtra, India; 3Department of Human Biology, University of Southern California, Los Angeles, CA, USACorrespondence: Shalini SrivastavaEnovate Biolife, 203, Morya Landmark, New Link Road, Andheri West, Mumbai, Maharashtra 400053, IndiaTel +919619477885Email shalini@enovatebiolife.comAim: The aim of the present study was to evaluate the effect of E-OA-07 on individuals having osteoarthritis of the knee.Background: Lanconone® (E-OA-07) is a widely marketed dietary supplement which has been previously studied in different clinical settings for managing chronic joint pain. This was a confirmatory study planned at a lowered dose regimen with the purpose of improving compliance and reducing consumer cost.Methods: Male and female participants aged between 40 and 65 years, with history of joint pain for at least 3 years, were recruited. Knee joint dysfunction of grade II/III was radiographically characterized as per Kellgren-Lawrence system of classification. Enrolled participants were randomized to receive E-OA-07 at a dose of 1000 mg/day or placebo over a period of 8 weeks. The primary efficacy parameter was assessment of change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. Whereas, the secondary parameters explored in the study included WOMAC subscales of stiffness and physical function, EQ-5D-5L questionnaire, systemic inflammatory marker (hs-CRP) and self-assessment of treatment satisfaction.Results: At the end of 8 weeks, joint pain severity as per WOMAC was found to be significantly reduced in the E-OA-07 group as compared to placebo (p

MicroRNA‐147 (miR‐147) had been previously found induced in synoviocytes by inflammatory stimuli derived from T cells in experimental arthritis. This study was designed to verify whether loss of its function might alleviate inflammatory events in joints of experimental and rheumatoid arthritis (RA). Dark Agouti (DA) rats were injected intradermally with pristane to induce arthritis, and rno‐miR‐147 antagomir was locally administrated into individual ankle compared with negative control or rno‐miR‐155‐5p antagomir (potential positive control). Arthritis onset, macroscopic severity, and pathological changes were monitored. While in vitro, gain or loss function of hsa‐miR‐147b‐3p/hsa‐miR‐155‐5p and ZNF148 was achieved in human synovial fibroblast cell line SW982 and RA synovial fibroblasts (RASF). The expression of miRNAs and mRNAs was detected by using RT‐quantitative PCR, and protein expression was detected by using Western blotting. Anti‐miR‐147 therapy could alleviate the severity, especially for the synovitis and joint destruction in experimental arthritis. Gain of hsa‐miR‐147b‐3p/hsa‐miR‐155‐5p function in TNF‐α stimulated SW982 and RASF cells could upregulate, in contrast, loss of hsa‐miR‐147b‐3p/hsa‐miR‐155‐5p function could downregulate the gene expression of TNF‐α, IL‐6, MMP3, and MMP13. Hence, such alteration could participate in synovial inflammation and joint destruction. RNAi of ZNF148, a miR‐147's target, increased gene expression of TNF‐α, IL‐6, MMP3, and MMP13 in SW982 and RASF cells. Also, mRNA sequencing data showed that hsa‐miR‐147b‐3p mimic and ZNF148 siRNA commonly regulated the gene expression of CCL3 and DEPTOR as well as some arthritis and inflammation‐related pathways. Taken together, miR‐147b‐3p contributes to synovial inflammation through repressing ZNF148 in RA and experimental arthritis. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) is a systemic chronic disease with synovial membrane, tendon and articular tissue inflammation. Current treatments of RA have many side effects and are quite expensive. Today, new treatments procedures and inexpensive herbal drugs are developed. Marham‐Mafasel is mainly made out of two traditional herbs (Arnebia euchroma and Martricaria chamomilla). Objective: In this study, for the first time, the impact of Marham‐Mafasel on joint inflammation, histopathological changes and IL‐1β gene expression was evaluated in RA animal model. Methods: The RA was induced by a single s.c. injection of 0.1 ml Freund's complete adjuvant into the left hind footpad. In continuous, 15 RA male Wistar rats were used in three groups: I: Control; II: Treatment I (Piroxicam) and III: Treatment II (Marham‐Mafasel). The volume of the hind paw was measured every day from 0 to 19 using water changed volume approach. The inflammation in the joint was evaluated using histopathology assay and gene expression of IL‐1β was evaluated with use of Real‐Time PCR. Results: Hind paw swelling of Marham‐Mafasel at days 10th and 19th was reduced compared with the control group (p < 0.05). There was no statistically difference in histological degrading and changes index in three groups (p ≥ 0.05). Relative expression of IL‐1β in Marham‐Mafasel group was significantly decreased compared with other groups. Conclusion: The co‐administration of M. Chamomile and A. euchroma, called Marham‐Mafasel, decreases IL‐1β gene expression that leads to a reduction in inflammation in rheumatoid arthritis (RA) animal model. [ABSTRACT FROM AUTHOR]