A new and spontaneous animal model for ankylosing spondylitis is found in cynomolgus monkeys.
Ontology highlight
ABSTRACT: Background
Ankylosing spondylitis is a progressive, disabling joint disease that affects millions worldwide. Given its unclear etiology, studies of ankylosing spondylitis relied heavily on drug-induced or transgenic rodent models which retain only partial clinical features. There is obviously a lack of a useful disease model to conduct comprehensive mechanistic studies.Methods
We followed a group of cynomolgus monkeys having joint lesions reported of spinal stiffness for 2 years by conducting hematological testing, radiographic examination, family aggregation analysis, pathological analysis, and genetic testing.Results
The results confirmed that these diseased animals suffered from spontaneous ankylosing spondylitis with clinical features recapitulating human ankylosing spondylitis disease progression, manifested by pathological changes and biochemical indicators similar to that of ankylosing spondylitis patients.Conclusion
The study offers a promising non-human primate model for spontaneous ankylosing spondylitis which may serve as an excellent substitute for its pre-clinical research.
SUBMITTER: Jia H
PROVIDER: S-EPMC8722021 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
Publications
A new and spontaneous animal model for ankylosing spondylitis is found in cynomolgus monkeys.
Jia Huanhuan H Chen Meili M Cai Yanzhen Y Luo Xiaoling X Hou Gang G Li Yongfeng Y Cai Chunmei C Chen Jun J Li Qingnan Q Miu Kai-Kei KK Fung Sin-Hang SH Wang Zhangting Z Huang Ren R Shen Huiyong H Lu Li L
Arthritis research & therapy 20220103 1
<h4>Background</h4>Ankylosing spondylitis is a progressive, disabling joint disease that affects millions worldwide. Given its unclear etiology, studies of ankylosing spondylitis relied heavily on drug-induced or transgenic rodent models which retain only partial clinical features. There is obviously a lack of a useful disease model to conduct comprehensive mechanistic studies.<h4>Methods</h4>We followed a group of cynomolgus monkeys having joint lesions reported of spinal stiffness for 2 years ...[more]
Similar Datasets
Project description:STUDY QUESTION:Does spontaneous endometriosis in cynomolgus monkeys have the characteristics required of a good experimental model? SUMMARY ANSWER:Spontaneous endometriosis in cynomolgus monkeys exhibited similar clinicopathological characteristics to the human disease and was useful as an experimental model. WHAT IS KNOWN ALREADY:The prevalence of endometriosis in autopsied cynomolgus monkeys (Macaca fascicularis) in a breeding colony was reported to be 28.7% in 1993. The histopathological findings we reported recently showed that components of spontaneous endometriosis were not only endometriotic epithelium and stromal cells (CD10-positive) with hemorrhage and inflammation, but also smooth muscle metaplasia and nerve fibers. STUDY DESIGN, SIZE, DURATION:During routine medical examinations at a research facility from 2008 to 2012, 614 female cynomolgus monkeys of reproductive age (6-25 years) were screened for endometriosis by the presence of regular menstrual bleeding, serum CA125 levels and palpation of the abdomen. In total, 29 monkeys were selected as subjects for the following study. PARTICIPANTS/MATERIALS, SETTING, METHODS:Of the 29 monkeys selected, 15 were diagnosed with endometriosis by laparoscopy and/or open surgery. The monkeys were monitored by observing their general condition, and eight of these were monitored using laparoscopy and MRI. In addition, to investigate appropriate screening parameters and endometriosis-associated biological parameters in monkeys, we retrospectively examined general laboratory parameters that correlate to the menstrual cycle and disease status. MAIN RESULTS AND THE ROLE OF CHANCE:The combination of CA125 serum levels (this was a useful marker for chocolate cysts), palpation of the abdomen, and fecal abnormalities was the most efficient screening method for diagnosing monkeys with endometriosis. Each animal could be diagnosed and assigned a disease stage by laparoscopy. While monitoring the disease stage by laparoscopy and/or MRI, disease status in individual monkeys was mainly stable or was progressive for 2-7 months. The detection rate by screening was low (15/614) but age-specific analysis suggests that screening would be more efficient if a colony for an endometriosis model is maintained with 11-20-year olds. As an endometriosis-associated biological parameter, the decrease in food consumption that coincided with menstruation was selected and correlated well (R2 value = 0.8239) with disease status (according to a modified adhesion revised American Fertility Society score). LARGE SCALE DATA:N/A. LIMITATIONS, REASONS FOR CAUTION:Peritoneal fluid was not analyzed because a smaller amount is produced in cynomolgus monkeys than in baboons. Although clinical endometriosis-associated pain is evaluated in women using a visual analog scale, pain could not be directly evaluated in this non-human primate model. WIDER IMPLICATIONS OF THE FINDINGS:Although cynomolgus monkeys are relatively small (2-5 kg) primates, laparoscopy and MRI make it possible to evaluate spontaneous endometriosis in these monkeys and to monitor its development over time. Spontaneous endometriosis in cynomolgus monkeys is a useful model for evaluating disease progress and drug efficacy because they have similar lesions to those in humans, and conventional laboratory methods and parameters for assessment are well established. STUDY FUNDING/COMPETING INTEREST(S):No external funds were used for this study. A.N.-K., K.T., H.T., A.K. and M.S. are full-time employees of Chugai Pharmaceutical Co., Ltd. R.K. received a consultancy fee from Chugai Pharmaceutical Co., Ltd. and lecture fees from Chugai Pharmaceuticals, Japan Vaccine Co. Ltd., Merck & Co., Mochida Co. Ltd., Roche Diagnostics, and BD, unrelated to the submitted work. S.N., S.O. and T.S. have nothing to declare.
| S-EPMC6012197 | biostudies-literature
Project description:Axial SpA (axSpA) is a common rheumatic disease characterized by inflammation leading to bone formation and functional impairment. TNF-α and IL-17 represent established targets in axSpA. TNF-α and IL-17 inhibitors have demonstrated efficacy in clinical trials and are currently approved biologic DMARDs for all subsets of the disease. Several lines of evidence implicate a role of an IL-23-IL-17 axis in the disease pathogenesis. In this light, and given the success of IL-17 blockade in axSpA, a similar good response to IL-23 was anticipated. Nevertheless, two clinical trials of anti-IL-23 monoclonal antibodies in axSpA have clearly exhibited negative results. This failure has raised theories for a degree of IL-23 independent pathway. The Janus kinase (JAK) pathway is also a potential therapeutic target, since several cytokines, including those involved in the IL-23-IL-17 axis, signal through the JAK family of tyrosine kinases. Further studies and more extended evaluation of response to cytokine inhibition across different tissues will be required to improve our understanding of SpA pathogenesis and determine its optimal management.
| S-EPMC8709566 | biostudies-literature
Project description:During toxicology studies, fasting animals prior to clinical pathology blood collection is believed to reduce variability in some clinical chemistry analytes. However, fasting adds stress to animals that are already stressed from the administration of potentially toxic doses of the test article. The purpose of this study was to assess the impacts of different fasting durations on cynomolgus monkeys' welfare during toxicology studies. To this end, we assessed the cynomolgus monkeys traditional and ancillary clinical pathology endpoints at different fasting times. We showed that most clinical pathology endpoints were largely comparable between different fasting times suggesting that cynomolgus monkeys could be fasted for as little as 4 hours for toxicology studies, as longer fasting times (up to 20 hours) resulted in stress, dehydration, and significant decreases in blood glucose- changes that impacts animal welfare. Shorter fasting times were associated with higher triglycerides variability among individual animals. Therefore, we propose that shorter fasting time (i.e., 4 hours) should be adequate for most toxicology studies except when: (1) parameters that could be affected by non-fasting conditions are important for safety and pharmacodynamic assessments (i.e., glucose and lipids) and (2) fasting would be needed for the bioavailability of an orally administered test article.
| S-EPMC10696910 | biostudies-literature
Project description:We have compared synovial biopsies from ankylosing spondylitis and undifferentiated spondylitis patients with healthy controls and osteoarthritis patients Objective: In spondylarthropies, whole-genome gene expression profiling studies have been limited to peripheral blood to date. By undertaking a study in knee synovial biopsies from spondylarthropy (SpA) and ankylosing spondylitis (AS) patients we aimed to identified joint-specific candidate genes and pathways. These pathways may mediate systemic inflammation driven joint damaging processes and more specifically, the osteoproliferation that is characteristic of these conditions. Methods: RNA was extracted from six seronegative SpA, two AS, three osteoarthritis (OA) and four normal control knee synovial biopsies. Whole genome expression profiling was undertaken using the Illumina DASL system, which assays 24000 cDNA probes. Differentially expressed candidate genes were then validated using quantitative PCR and immunohistochemistry. Results: 416 differentially expressed genes were identified that clearly delineated between AS/SpA and control groups. Pathway analysis showed altered gene-expression in oxidoreductase activity, osteoblast activity, B-cell associated, matrix catabolic, and metabolic pathways. The inflammatory mediator, MMP3, was strongly upregulated in AS/SpA samples and the Wnt pathway inhibitors DKK3 and Kremen1 were downregulated. Conclusion: Pathways mediating both systemic inflammation as well as local tissue changes were identified. This suggests initial systemic inflammation in spondylarthropies transfers to and persists in the local joint environment, subsequently mediating changes in genes directly involved in the destructive tissue remodelling. Fifteen knee synovial biopsy tissue samples consisting of six seronegative spondyloarthropy (SpA), two ankylosing spondylitis (AS), three osteoarthritis (OA) and four normal control biopsies were obtained from the Synovial Tissue Bank at the Repatriation General Hospital in Adelaide, South Australia with the appropriate ethical approval (Supplementary Table 1). All patients provided informed written consent.
2012-12-01 | E-GEOD-41038 | biostudies-arrayexpress
Project description:Background: The pathogenesis and diagnosis of Ankylosing Spondylitis (AS) has remained uncertain due to several reasons, including the lack of studies on the local and systemic immune response in AS. To construct a clinical diagnostic model, this study identified the micro RNA-messenger RNA (miRNA-mRNA) interaction network and immune cell infiltration-related hub genes associated with AS. Materials and Methods: Total RNA was extracted and purified from the interspinous ligament tissue samples of three patients with AS and three patients without AS; miRNA and mRNA microarrays were constructed using the extracted RNA. Bioinformatic tools were used to construct an miRNA-mRNA network, identify hub genes, and analyze immune infiltration associated with AS. Next, we collected the blood samples and clinical characteristics of 359 patients (197 with AS and 162 without AS). On the basis of the clinical characteristics and results of the routine blood tests, we selected immune-related cells whose numbers were significantly different in patients with AS and patients without AS. Univariate and multivariate logistic regression analysis was performed to construct a nomogram. Immunohistochemistry staining analysis was utilized to verify the differentially expression of LYN in AS and controls. Results: A total of 225 differentially expressed miRNAs (DE miRNAs) and 406 differentially expressed mRNAs (DE mRNAs) were identified from the microarray. We selected 15 DE miRNAs and 38 DE mRNAs to construct a miRNA-mRNA network. The expression of LYN, an immune-related gene, correlated with the counts of monocytes, neutrophils, and dendritic cells. Based on the independent predictive factors of sex, age, and counts of monocytes, neutrophils, and white blood cells, a nomogram was established. Receiver operating characteristic (ROC) analysis was performed to evaluate the nomogram, with a C-index of 0.835 and AUC of 0.855. Conclusion: LYN, an immune-related hub gene, correlated with immune cell infiltration in patients with AS. In addition, the counts of monocytes and neutrophils were the independent diagnostic factors for AS. If verified in future studies, a diagnostic model based on these findings may be used to predict AS effectively.
| S-EPMC9575679 | biostudies-literature
Project description:BackgroundAnkylosing spondylitis (AS) is a chronic rheumatic disease that predominantly affects the axial skeleton, causing pain and functional impairment. Kinesiophobia, or fear of movement, is common in patients with chronic pain conditions and can significantly hinder treatment outcomes. This study aims to assess the level of kinesiophobia in AS patients and explore its relationship with demographic characteristics, disease duration, pain intensity, disease activity, and functional impairment.MethodsThis single-center study included 35 AS patients from July 2021 to July 2023. Patient demographics, disease duration, disease activity (BASDAI (Bath Ankylosing Spondylitis Disease Activity Index)), functionality (BASFI (Bath Ankylosing Spondylitis Functional Index)), pain intensity (VAS (Visual Analog Scale)), and kinesiophobia (TSK (Tampa Scale of Kinesiophobia)) were recorded and analyzed. Patients were categorized into low and high kinesiophobia groups based on TSK scores.ResultsOf the 35 AS patients, 15 (42.86%) had high kinesiophobia levels (TSK ≥37). Patients with high kinesiophobia had significantly higher BASDAI, BASFI, and VAS scores (p < 0.001) compared to those with low kinesiophobia. No significant relationship was found between kinesiophobia and age, gender, or disease duration (p > 0.05).ConclusionHigh levels of kinesiophobia in AS patients are associated with increased pain, disease activity, and functional impairment. Early interventions targeting kinesiophobia could improve treatment outcomes and patient functionality.
| S-EPMC11830361 | biostudies-literature
Project description:Ankylosing spondylitis (AS) is a complex disease involving multiple risk factors, both genetic and environmental. AS patients are predominantly young men, and the disease is characterized by inflammation and ankylosis, mainly at the cartilage-bone interface and enthesis. HLA-B27 has been known to be the major AS-susceptibility gene for more than 40 years. Despite advances made in the past few years, progress in the search for non-human leukocyte antigen susceptibility genes has been hampered by the heterogeneity of the disease. Compared to other complex diseases, such as inflammatory bowel disease (IBD), fewer susceptibility loci have been identified in AS. Furthermore, non-major histocompatibility-complex susceptibility loci discovered, such as ERAP1 and IL23R, are likely contributors to joint inflammation. Identification and confirmation of functional variants remains a significant challenge of investigations involving genome-wide association studies (GWAS). It remains unclear why none of the AS-susceptibility genes identified in GWAS appear to be directly involved in the ankylosing process. Numerous reviews have recently been published on the genetics of AS. Therefore, aside from a brief summary of what AS GWAS has successfully achieved thus far, this review will focus on directions that could address unanswered questions raised by GWAS.
| S-EPMC4070859 | biostudies-literature
Project description:We have compared synovial biopsies from ankylosing spondylitis and undifferentiated spondylitis patients with healthy controls and osteoarthritis patients Objective: In spondylarthropies, whole-genome gene expression profiling studies have been limited to peripheral blood to date. By undertaking a study in knee synovial biopsies from spondylarthropy (SpA) and ankylosing spondylitis (AS) patients we aimed to identified joint-specific candidate genes and pathways. These pathways may mediate systemic inflammation driven joint damaging processes and more specifically, the osteoproliferation that is characteristic of these conditions. Methods: RNA was extracted from six seronegative SpA, two AS, three osteoarthritis (OA) and four normal control knee synovial biopsies. Whole genome expression profiling was undertaken using the Illumina DASL system, which assays 24000 cDNA probes. Differentially expressed candidate genes were then validated using quantitative PCR and immunohistochemistry. Results: 416 differentially expressed genes were identified that clearly delineated between AS/SpA and control groups. Pathway analysis showed altered gene-expression in oxidoreductase activity, osteoblast activity, B-cell associated, matrix catabolic, and metabolic pathways. The inflammatory mediator, MMP3, was strongly upregulated in AS/SpA samples and the Wnt pathway inhibitors DKK3 and Kremen1 were downregulated. Conclusion: Pathways mediating both systemic inflammation as well as local tissue changes were identified. This suggests initial systemic inflammation in spondylarthropies transfers to and persists in the local joint environment, subsequently mediating changes in genes directly involved in the destructive tissue remodelling.
2012-12-01 | GSE41038 | GEO
Project description:Whole blood RNA-sequencing data from 5 AS patients who met 1984 AS criteria and 3 healthy human were obtained to gain insight into the potential mechanism of ankylosing spondylitis.
2021-11-10 | GSE181364 | GEO
Project description:Hepcidin (H25) is a hormone peptide synthesized by the liver that binds to ferroportin and blocks iron export. In this study, H25 was inhibited by administration of single and multiple doses of an anti-H25 monoclonal antibody Ab 12B9m in cynomolgus monkeys. The objective of this analysis was to develop a pharmacodynamic model describing the role of H25 in regulating iron homeostasis and the impact of hepcidin inhibition by Ab 12B9m. Total serum H25 and Ab 12B9m were determined in each animal. Corresponding measurements of serum iron and hemoglobin (Hb) were obtained. The PD model consisted of iron pools in serum (FeS), reticuloendothelial macrophages (FeM), hemoglobin (FeHb), and liver (FeL). The iron was assumed to be transported between the FeS, FeHb, and FeM unidirectionally at rates k S, k Hb, and k M. H25 serum concentrations were described by the previously developed PK model with the parameters fixed at their estimates. The serum iron and Hb data were fitted simultaneously. The corresponding estimates of the rate constants were k S/Fe0 = 0.113 h(-1), k M = 0.00191 h(-1), and k Hb = 0.00817 h(-1). The model-based IC50 value for the H25 inhibitory effect on ferroportin activity was 0.398 nM. The PD model predicted a negligible effect of Ab 12B9m on Hb levels for the tested doses. The presented PD model adequately described the serum iron time courses following single and multiple doses of Ab 12B9m. Ab 12B9m-induced inhibition of H25 resulted in a temporal increase in serum and liver iron and a decrease in the iron stored in reticuloendothelial macrophages.
| S-EPMC5256605 | biostudies-literature