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Dual therapeutic targeting of intra-articular inflammation and intracellular bacteria enhances chondroprotection in septic arthritis.

ABSTRACT: Bacterial infections involving joints and vital organs represent a challenging clinical problem because of the two concurrent therapeutic goals of bacterial eradication and tissue preservation. In the case of septic arthritis, permanent destruction of articular cartilage by intense host inflammation is commonly seen even after successful treatment of bacterial infection. Here, we provide scientific evidence of a novel treatment modality that can protect articular cartilage and enhanced eradication of causative bacteria in septic arthritis. Locally delivered cell-penetrating antibiotics such as rifampicin effectively eradicate intracellular reservoirs of methicillin-resistant Staphylococcus aureus within joint cells. Furthermore, mitigation of intra-articular inflammation by targeting the NLRP3 (nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3) inflammasome protects articular cartilage from damage in a murine model of knee septic arthritis. Together, concurrent mitigation of intra-articular inflammation and local adjuvant targeting of intracellular bacteria represents a promising new therapeutic strategy for septic arthritis.

SUBMITTER: Kwon HK

PROVIDER: S-EPMC8232912 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionAdrenomedullin is a potent vasodilatory and hypotensive peptide as well as an endogenous immunomodulatory factor with predominantly anti-inflammatory effects. The purpose of the present study was to evaluate the therapeutic effects of adrenomedullin in rabbits with antigen-induced arthritis, an experimental model of rheumatoid arthritis.MethodsFollowing the induction of arthritis in both knee joints by ovalbumin injection into the joint spaces of pre-immunized rabbits, increasing daily doses of adrenomedullin were injected into the knee joint spaces or saline was injected into the contralateral knee joint spaces as the control. For time-course experiments, adrenomedullin and saline were injected into the knee joint spaces daily for 7 days and 20 days. The degree of joint swelling and the histological change in the knee joints injected with adrenomedullin were compared with the control knee joints. Histological evaluation of the infrapatellar fat pads and synovial tissue was performed. TNFalpha, IL-6, vascular endothelial growth factor and transforming growth factor-beta mRNA levels in the synovial tissue were measured using real-time quantitative PCR.ResultsDaily injections of adrenomedullin into the knee joint spaces of rabbits with antigen-induced arthritis decreased joint swelling. Histological examination revealed that adrenomedullin reduced edematous changes and the infiltration of inflammatory cells in the synovial tissues. Analysis of mRNA levels showed that adrenomedullin significantly reduced TNFalpha mRNA expression by 21% to 49% in a dose-dependent manner, and dose-dependently increased IL-6 mRNA expression by 45% to 121%.ConclusionsThese results suggest that daily injections of adrenomedullin into the knee joint spaces of rabbits with antigen-induced arthritis ameliorated the inflammatory response in arthritic joints. Adrenomedullin may thus be useful as a treatment for rheumatoid arthritis; however, the effect of adrenomedullin on IL-6 production in the synovial tissue may be an undesirable adverse effect in rheumatoid arthritis therapy.

Project description:Arthritic diseases, such as osteoarthritis and rheumatoid arthritis, inflict an enormous health care burden on society. Osteoarthritis, a degenerative joint disease with high prevalence among older people, and rheumatoid arthritis, an autoimmune inflammatory disease, both lead to irreversible structural and functional damage to articular cartilage. The aim of this study was to investigate the effect of polyphenols such as catechin, quercetin, epigallocatechin gallate, and tannic acid, on crosslinking type II collagen and the roles of these agents in managing in vivo articular cartilage degradation. The thermal, enzymatic, and physical stability of bovine articular cartilage explants following polyphenolic treatment were assessed for efficiency. Epigallocatechin gallate and tannic acid-treated explants showed >12 °C increase over native cartilage in thermal stability, thereby confirming cartilage crosslinking. Polyphenol-treated cartilage also showed a significant reduction in the percentage of collagen degradation and the release of glycosaminoglycans against collagenase digestion, indicating the increase physical integrity and resistance of polyphenol crosslinked cartilage to enzymatic digestion. To examine the in vivo cartilage protective effects, polyphenols were injected intra-articularly before (prophylactic) and after (therapeutic) the induction of collagen-induced arthritis in rats. The hind paw volume and histomorphological scoring was done for cartilage damage. The intra-articular injection of epigallocatechin gallate and tannic acid did not significantly influence the time of onset or the intensity of joint inflammation. However, histomorphological scoring of the articular cartilage showed a significant reduction in cartilage degradation in prophylactic- and therapeutic-groups, indicating that intra-articular injections of polyphenols bind to articular cartilage and making it resistant to degradation despite ongoing inflammation. These studies establish the value of intra-articular injections of polyphenol in stabilization of cartilage collagen against degradation and indicate the unique beneficial role of injectable polyphenols in protecting the cartilage in arthritic conditions.

Project description:BackgroundJuvenile Idiopathic Arthritis (JIA) commonly affects joints of the lower limb including the knee, ankle, subtalar and other foot joints. Intra-articular corticosteroid injections (IACIs) are considered to be effective for short-term relief of synovitis, however, there appears to be a significant lack of published evidence from comparative effectiveness studies. The aim of this study was to identify and critically appraise the evidence for the efficacy of lower limb IACIs in children/adolescents with JIA.MethodsStudies were identified in databases Medline, Embase, CINAHL, AMED, PEDro, the Cochrane Library and TRIP, with no date restrictions. The primary search terms 'juvenile idiopathic arthritis', 'lower limb', 'knee'; 'ankle', 'foot' and 'intra-articular steroid injections' and related synonyms were used to develop a comprehensive pragmatic literature search strategy. Included studies were quantitative longitudinal design such as randomised controlled trials, pseudo-randomised and non-randomised experimental studies, cohort studies, and case-control studies. All outcomes measures were subject to analysis. Quality assessment was conducted using the Cochrane Collaboration criteria with additional criteria for sample population representativeness, quality of statistical analysis and compliant intervention use and presence of co-interventions. Qualitative data synthesis was conducted for the outcome domains. Meta-analyses were not possible as multiple randomised controlled trials for outcome measures were not available. Levels of evidence were assigned to each outcome measure.ResultsThe inclusion criteria were met by twenty-one studies. One study had high quality for internal validity and nine studies had high quality for external validity. No studies had high quality for both internal and external validity. Four outcome domains were identified. There was weak evidence for IACIs decreasing clinical signs and symptoms in the lower leg, improving joint range of motion, decreasing leg length discrepancy, and for imaging techniques detecting the effects of IACIs.ConclusionsThere is some weak evidence for the efficacy of IACIs improving certain outcome measures. However, there is also some inconclusive evidence due to a lack of quality studies. More high quality evidence is necessary to definitely determine the efficacy of IACIs for JIA in the lower leg.

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Dual therapeutic targeting of intra-articular inflammation and intracellular bacteria enhances chondroprotection in septic arthritis.

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