Dataset Information

Variations in gene expression levels with severity of synovitis in dogs with naturally occurring stifle osteoarthritis.

ABSTRACT: Osteoarthritis (OA) is one of the major causes of chronic pain in dogs. However, the pathogenesis of OA has not been fully understood in dogs. The objective of this study was to comprehensively investigate the mRNA expression levels of proinflammatory cytokines, inflammatory mediators, nerve growth factor and its receptor, and matrix metalloproteinases in the synovium of dogs with spontaneous OA as well as to elucidate their relationships with the severity of synovitis. Dogs that were diagnosed with stifle OA on the basis of radiographic findings were included, and the degree of synovitis was observed using stifle arthroscopy. The dogs were assigned to two different groups depending on their synovitis scores: the low-grade group (score of 1 or 2; n = 8) and high-grade group (score of 3 to 5; n = 18). The dogs showing no evidence of orthopedic disease were included in the control group (n = 6). Synovial tissue samples were collected from the sites at which synovitis scores were assessed using arthroscopy. Total RNA was extracted from the collected synovial tissue, and cDNA was synthesized. Subsequently, RT-qPCR were performed using canine-specific primer sets for IL1B, IL6, CXCL8, TNF, TGFB1, PTGS2, PTGES, MMP3, MMP13, NGF, NTRK1, and PTGER4. Expression levels of IL1B, IL6, CXCL8, and MMP13 were significantly higher in the high-grade group than in the control group. In addition, expression levels of IL1B, CXCL8, TNF, and PTGS2 were significantly higher in the high-grade group than in the low-grade group. Expression levels of IL1B, IL6, CXCL8, TNF, PTGS2, and PTGER4 showed significant positive correlation with synovitis score. In conclusion, all mRNA expression levels in the synovial membrane varied according to the degree of synovitis in dogs with spontaneous OA. Thus, this study may partially elucidate the pathogenesis of synovitis in dogs with spontaneous OA.

SUBMITTER: Yamazaki A

PROVIDER: S-EPMC7842980 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Variations in gene expression levels with severity of synovitis in dogs with naturally occurring stifle osteoarthritis.

Yamazaki Atsushi A Edamura Kazuya K Tomo Yuma Y Seki Mamiko M Asano Kazushi K

PloS one 20210128 1

Osteoarthritis (OA) is one of the major causes of chronic pain in dogs. However, the pathogenesis of OA has not been fully understood in dogs. The objective of this study was to comprehensively investigate the mRNA expression levels of proinflammatory cytokines, inflammatory mediators, nerve growth factor and its receptor, and matrix metalloproteinases in the synovium of dogs with spontaneous OA as well as to elucidate their relationships with the severity of synovitis. Dogs that were diagnosed ...[more]

PMID: 33507995

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Project description:The purpose of this study was to evaluate matrix metalloproteinases (MMP) -2 and MMP-3 in serum, and keratinocyte-derived chemoattractant (KC), interleukin 8 (IL-8) and monocyte chemoattractant 1 (MCP-1) in synovial fluid (SF) as stifle osteoarthritis (OA) biomarkers in dogs. Dogs with naturally occurring cranial cruciate ligament (CrCL) rupture (OA group) and healthy controls were recruited. Stifles with CrCL deficiency were surgically stabilized. Serum, SF, and synovial biopsy samples were collected from the OA group preoperatively, whereas samples were collected once from control dogs. A blinded veterinary pathologist graded synovial biopsies. Serum and SF analyses were performed using xMAP technology. General linear regression was used for statistical comparisons of serum biomarkers, and mixed linear regression for SF biomarkers and temporal concentration changes. The overall discriminative ability was quantified using area under curve (AUC). Spearman's correlation coefficient was used to assess correlations between synovial histology grades and the biomarkers. Samples from 62 dogs in the OA group and 50 controls were included. The MMP-2 and MMP-3 concentrations between the OA and control groups were not significantly different, and both with an AUC indicating a poor discriminative ability. All three SF biomarker concentrations were significantly different between the OA group and controls (P <0.05). The MCP-1 was the only biomarker showing an acceptable discriminative performance with an AUC of 0.91 (95% confidence interval: 0.83-0.98). The sum of the inflammatory infiltrate score was significantly correlated with all three SF biomarkers (P <0.01). Summed synovial stroma, and all scores combined were significantly correlated with IL-8 and MCP-1 concentrations (P <0.003), and the summed synoviocyte scores were significantly correlated with MCP-1 concentrations (P <0.001). Correlations between MCP-1 concentrations and synovial histopathologic grading and its discriminative ability suggest its potential as a synovitis biomarker in canine stifle OA associated with CrCL rupture.

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Project description:RationaleBarriers to developing treatments for human status epilepticus include the inadequacy of experimental animal models. In contrast, naturally occurring canine epilepsy is similar to the human condition and can serve as a platform to translate research from rodents to humans. The objectives of this study were to characterize the pharmacokinetics of an intravenous (IV) dose of topiramate (TPM) in dogs with epilepsy and evaluate its effect on intracranial electroencephalographic (iEEG) features.MethodsFive dogs with naturally occurring epilepsy were used for this study. Three were getting at least one antiseizure drug as maintenance therapy including phenobarbital (PB). Four (ID 1-4) were used for the 10 mg/kg IV TPM + PO TPM study, and three (ID 3-5) were used for the 20 mg/kg IV TPM study. IV TPM was infused over 5 min at both doses. The animals were observed for vomiting, diarrhea, ataxia, and lethargy. Blood samples were collected at scheduled pre- and post-dose times. Plasma concentrations were measured using a validated high-performance liquid chromatography-mass spectrometry method. Non-compartmental and population compartmental modeling were performed (Phoenix WinNonLin and NLME) using plasma concentrations from all dogs in the study. iEEG was acquired in one dog. The difference between averaged iEEG energy levels at 15 min pre- and post-dose was assessed using a Kruskal-Wallis test.ResultsNo adverse events were noted. TPM concentration-time profiles were best fit by a two compartment model. PB co-administration was associated with a 5.6-fold greater clearance and a ~4-fold shorter elimination half-life. iEEG data showed that TPM produced a significant energy increase at frequencies >4 Hz across all 16 electrodes within 15 min of dosing. Simulations suggested that dogs on an enzyme inducer would require 25 mg/kg, while dogs on non-inducing drugs would need 20 mg/kg to attain the target concentration (20-30 μg/mL) at 30 min post-dose.ConclusionThis study shows that IV TPM has a relatively rapid onset of action, loading doses appear safe, and the presence of PB necessitates a higher dose to attain targeted concentrations. Consequently, it is a good candidate for further evaluation for treatment of seizure emergencies in dogs and people.

Dataset Information

Variations in gene expression levels with severity of synovitis in dogs with naturally occurring stifle osteoarthritis.

Publications

Variations in gene expression levels with severity of synovitis in dogs with naturally occurring stifle osteoarthritis.

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