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Mean bone density in the bones of control and CIA mice. Shown are the mean densities and standard errors over time for (A) femur, (B) humerus, and (C) tibia from control and CIA mouse groups. P values were calculated by comparing each pair of control and CIA densities for each scan time (week 0, week 4, week 7, and week 9), and statistical significance was considered significant (*) if P < 0.05.
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Inflammatory arthritis is a chronic disease, resulting in synovitis and subchondral and bone area destruction, which can severely affect a patient's quality of life. The most common form of inflammatory arthritis is rheumatoid arthritis (RA) in which many of the disease mechanisms are not well understood. The collagen-induced arthritis (CIA) mouse...
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Context 1
... of the segmenta- tion CT slices through left femurs of a control and CIA mouse at week 0 are shown in Figure 2. We calculated the mean bone density of femur, humerus, and tibia bones from the CT images. As shown in Figure 3A, the mean bone density of femurs in control mice increased by 25.4% between weeks 0 and 9. In contrast, during the same period the mean bone density of femurs in CIA mice in- creased only 15.8%. ...Context 2
... mean bone density between the two groups was not significantly different at week 0, we observed statistically significant differences during subse- quent scans at weeks 4, 7, and 9. In a similar fashion, the mean bone density of the humerus bones in the control mice increased by 29% between weeks 0 and 9 ( Figure 3B). In contrast, the mean bone density of the humerus bones in the CIA mice increased only 20.9% between weeks 0 and 9; however significant difference was observed only at week 7. Finally, the mean bone density of tibia bones from control mice increased by 25.1% ( Figure 3C). ...Context 3
... a similar fashion, the mean bone density of the humerus bones in the control mice increased by 29% between weeks 0 and 9 ( Figure 3B). In contrast, the mean bone density of the humerus bones in the CIA mice increased only 20.9% between weeks 0 and 9; however significant difference was observed only at week 7. Finally, the mean bone density of tibia bones from control mice increased by 25.1% ( Figure 3C). In contrast, CIA mice showed only a modest 15.8% increase during the same period that reached statistical significance at weeks 7 and 9. ...Similar publications
Regarding the persistence of subclinical synovitis, the concept of ultrasound remission has been proposed in addition to clinical remission. The present study aims to explore whether ultrasound remission has predictive value and ultrasound remission at which time point has predictive value for good structural outcome. Collagen-induced arthritis (CI...
Citations
... Radiographic deterioration in RA is characterized by the degree of articular damage and the presence of distinct lesions such as joint space narrowing, bone erosion, and osteoporosis, as revealed through diagnostic imaging modalities including X-rays, magnetic resonance imaging, or computed tomography scans (96). The quantification and prognostication of structural joint impairment traditionally hinge on clinical expertise, underscoring the necessity for an automated, bias-free evaluation method. ...
Rheumatoid arthritis (RA) is an autoimmune disease causing progressive joint damage. Early diagnosis and treatment is critical, but remains challenging due to RA complexity and heterogeneity. Machine learning (ML) techniques may enhance RA management by identifying patterns within multidimensional biomedical data to improve classification, diagnosis, and treatment predictions. In this review, we summarize the applications of ML for RA management. Emerging studies or applications have developed diagnostic and predictive models for RA that utilize a variety of data modalities, including electronic health records, imaging, and multi-omics data. High-performance supervised learning models have demonstrated an Area Under the Curve (AUC) exceeding 0.85, which is used for identifying RA patients and predicting treatment responses. Unsupervised learning has revealed potential RA subtypes. Ongoing research is integrating multimodal data with deep learning to further improve performance. However, key challenges remain regarding model overfitting, generalizability, validation in clinical settings, and interpretability. Small sample sizes and lack of diverse population testing risks overestimating model performance. Prospective studies evaluating real-world clinical utility are lacking. Enhancing model interpretability is critical for clinician acceptance. In summary, while ML shows promise for transforming RA management through earlier diagnosis and optimized treatment, larger scale multisite data, prospective clinical validation of interpretable models, and testing across diverse populations is still needed. As these gaps are addressed, ML may pave the way towards precision medicine in RA.
... Although the pathogenesis of RArelated OP is uncertain, it is evident that the RANK/RANKL/OPG and Wnt/DKK-1/sclerostin pathways and certain proinflammatory cytokines are crucial in its development (Llorente et al., 2020). Micro-CT provides a non-invasive approach to evaluate alterations in bone structure in the CIA mouse model (Yang et al., 2013). While the method is most often deployed at the peak of inflammation, which is around the sixth-eighth week postimmunization, the present study offers data from mice in which obvious inflammation has already decreased. ...
Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory disorder with high prevalence among middle-aged women. Collagen-induced arthritis (CIA) is the most widely used animal model of RA, however, sex differences and long-term effects of CIA in mice are poorly described in the literature.
Aim: Therefore, the present study aimed to analyze the long-term effects of CIA on the joints of middle-aged mice of both sexes and to describe potential sex differences.
Materials and methods: CIA was induced in middle-aged DBA/1J mice by immunization with bovine type II collagen and complete Freund’s adjuvant. Saline was administered to control mice. Arthritis score assessment, plethysmometry, and thermal imaging of the joints were performed weekly for 15 weeks. Locomotor activity, micro-computed tomography, joint histology and biochemical analyses were performed at the end of the experiment.
Results: Our results indicate a similar prevalence of arthritis in both sexes of mice—67% (8/12) of females and 89% (8/9) males with an earlier onset in males (day 14 vs. day 35). After the arthritis scores peaked on day 56 for males and day 63 for females, they steadily declined until the end of the experiment on day 105. A similar dynamics was observed in paw volume and temperature analyzing different aspects of joint inflammation. Long-term consequences including higher proteinuria (by 116%), loss of bone density (by 33.5%) and joint damage in terms of synovial hyperplasia as well as bone and cartilage erosions were more severe in CIA males compared to CIA females. There were no significant differences in locomotor activity between CIA mice and CTRL mice of any sex.
Conclusion: This is the first study to describe the long-term effects of the CIA model in terms of sex differences in DBA/1J mice. Our results indicate sex differences in the dynamics, but not in the extent of arthritis. An earlier onset of arthritis and more severe consequences on joints, bones and kidneys were found in males. The underlying immune pathomechanisms responsible for the limited duration of the arthritis symptoms and the opposite sex difference in comparison to RA patients require further investigation.
... The time for RA induction in this study was approximately 35 days, which was sufficient time to induce an inflammatory response in the joint, but it might be not enough to induce bone-related symptoms. Also, considering that, in mouse, CIA can be induced only in susceptible strain such as DBA/1, B10 [21], further studies will be required to induce a more sophisticated RA model in minipigs. ...
Background:
Rheumatoid arthritis (RA) is a chronic inflammatory disease of joint, but there is no known cure. 3'-sialyllactose (3'-SL) is an oligosaccharide that is abundant in breast milk of mammals, and has anti-inflammatory properties. However, the efficacy of 3'-SL on RA remains unclear. The objective of the present study was to evaluate the therapeutic effect of 3'-SL after it was directly injected into the knee joint cavity of a RA minipig model.
Results:
Minipig RA model was induced by intra-articular injection of bovine type II collagen emulsified with complete or incomplete Freund's adjuvant into left knee joint. In clinical assessment, lameness and swelling of the hindlimb and increased knee joint width were observed in all animals. After the onset of arthritis, 3'-SL (0, 2, 10, and 50 mg/kg) was directly administered to the left knee joint cavity once a week for 4 weeks. Compared to the vehicle control group, no significant difference in macroscopic observation of the synovial pathology or the expression of inflammation-related genes (IL-1β, TNF-α, and COX2) in the synovial membrane of the knee joint was found. In microscopic observation, cell cloning of the articular cartilage was significantly reduced in proportion to the concentration of 3'-SL administered.
Conclusions:
Our results suggest that intra-articular injected 3'-SL had a therapeutic effect on collagen-induced arthritis at the cellular level with potential as a medication for RA.
... In vivo µCT affords the ability to evaluate bone erosion and inflammation through soft tissue volume (STV) changes, while also providing for longitudinal studies, reducing the number of animals needed. This versatile tool can be used to monitor anatomical changes in vivo and findings have demonstrated µCT to be a viable, efficient, and sensitive method to characterize disease progression 11 . ...
... Previously, in vivo µCT studies have primarily been used to validate µCT against other readouts using naïve animals or to compare naïve and diseased animals. In vivo µCT has been found to be sensitive enough to identify changes in morphology associated with disease, suggesting that any treatment-associated changes could also be identified 11,14 . In this study, we present quantitative assessment of bone and soft tissue changes throughout disease progression and in response to treatment using high-resolution in vivo µCT and correlate them to traditional caliper measurements and histopathology assessment. ...
A painful, chronic condition, Rheumatoid Arthritis, is marked by bone erosion and soft tissue swelling at the joint. As treatments are investigated in pre-clinical models, characterizing disease progression is integral to assessing treatment efficacy. Here, in vivo and ex vivo micro-computed tomography (µCT) are used in parallel with traditional caliper score measurement to quantify physiological changes in the tarsal region in a murine, collagen-induced arthritis model. In vivo imaging methods, which are validated here through comparison to ex vivo and caliper methods, afford longitudinal analysis of both bone and soft tissue through a single image acquisition. This method removes the subjectivity of swelling quantification which is inherently associated with traditional caliper measurements. Histopathology offers an additional assessment of bone erosion and inflammation by providing a microscopic characterization of disease activity. In comparison to untreated animals, daily prednisolone (glucocorticoid) treatment is shown to restore bone volume, as reflected through in vivo and ex vivo µCT images, as well as histopathology. Prednisolone-associated reduction in inflammation is shown through in vivo µCT soft tissue volume measurements, paw caliper measurements, and histopathology. The findings reported here provide a comprehensive validation of in vivo µCT with a sensitivity that enables characterization of pre-clinical disease assessment in response to treatment in a murine, collagen-induced arthritis model.
... The latter included infiltration of neutrophils, macrophages, CD4+ or CD8+ T cells, and B cells at the site of inflammation. These clinical signs are reminiscent of human RA and of the experimental RA mouse models, CIA, AIA, and CAIA model (56)(57)(58). It has been shown that paw swelling in the DTHA model depends on the presence and activity of CD4+ T cells and can be augmented by depletion of regulatory T cells (Tregs) (20,44). ...
Delayed-type hypersensitivity arthritis (DTHA) is a recently established experimental model of rheumatoid arthritis (RA) in mice with pharmacological values. Despite an indispensable role of CD4+ T cells in inducing DTHA, a potential role for CD4+ T cell subsets is lacking. Here we have quantified CD4+ subsets during DTHA development and found that levels of activated, pro-inflammatory Th1, Th17, and memory CD4+ T cells in draining lymph nodes were increased with differential dynamic patterns after DTHA induction. Moreover, according to B-cell depletion experiments, it has been suggested that this cell type is not involved in DTHA. We show that DTHA is associated with increased levels of B cells in draining lymph nodes accompanied by increased levels of circulating IgG. Finally, using the anti-rheumatoid agents, methotrexate (MTX) and the anti-inflammatory drug dexamethasone (DEX), we show that MTX and DEX differentially suppressed DTHA-induced paw swelling and inflammation. The effects of MTX and DEX coincided with differential regulation of levels of Th1, Th17, and memory T cells as well as B cells. Our results implicate Th1, Th17, and memory T cells, together with activated B cells, to be involved and required for DTHA-induced paw swelling and inflammation.
... In the present study, CIA mice showed histological features similar to those of human RA patients 36,37 . These features, including joint deformity, cartilage loss, and bone erosion, were further confirmed by μCT analyses. ...
The mechanism underlying bee venom (BV) therapy is still controversial, with opinions ranging from constituent-based pharmacological action to homeopathic-like activity. The purpose of this study was to examine whether BV phospholipase A2 (bvPLA2), an enzymatic component of BV, is a novel anti-inflammatory and anti-arthritic mediator capable of stimulating CD25 ⁺ Foxp3 ⁺ regulatory T cell (Treg) polarization in a mouse model of human rheumatoid arthritis (RA). An experimental model of RA was established in male DBA/1 mouse by 2-week-interval injections of 100 μg type II collagen emulsified in complete (first injection) or incomplete Freund’s adjuvant (second injection) at the base of the tail. During arthritis development, bvPLA2 (0.1, 0.5, 1.0 mg/kg) and/or Treg inhibitors such as anti-CD25 antibodies and peptide 60 (P60) were injected intraperitoneally for 5 weeks. Arthritic symptoms and the expansion of Tregs were then assessed by behavioral assessments, histological and micro-CT imaging, and flow cytometry. bvPLA2 injections significantly alleviated arthritic behaviors such as squeaking and joint swelling, consistent with changes seen on both histological and micro-CT images. The anti-arthritic effects of bvPLA2 were blocked by intraperitoneal injections of 0.25 mg/kg anti-CD25 antibody and 10 μg/kg P60, as determined by behavioral assessments. Flow cytometric analysis of dendritic cells, B cells, and major T cell subsets from spleens revealed a significant depletion of Tregs following anti-CD25 antibody, but not P60, treatment. bvPLA2 treatment exerted significant anti-inflammatory and anti-arthritic activities in a mouse model of RA via the induction of Tregs.
... Abbreviations: CIA, collagen-induced arthritis; CT, computed tomography; ETN, etanercept; RCI, repository corticotropin injection histologically in preclinical models [46]. Blockade of TNF-α is not efficacious at decreasing humoral autoimmunity, and in fact has been reported to increase Ig levels in CIA [47,48] and in humans with RA [49,50]. The combination of RCI with ETN effectively decreased anti-CII Ig levels in CIA rats. ...
Background:
Melanocortin receptor (MCR) agonists have anti-inflammatory and immunomodulatory properties mediated by receptors expressed on cells relevant to arthritis. Repository corticotropin injection (RCI; Acthar® Gel), an MCR agonist preparation, is approved as adjunctive therapy for rheumatoid arthritis (RA), but its mechanism of action in RA is unclear. This study explored the efficacy of RCI as monotherapy or adjunctive therapy with etanercept (ETN) in an established animal model of collagen-induced arthritis (CIA).
Methods:
After induction of CIA, rats (n = 10 per group) were randomized to receive subcutaneous RCI (40, 160, or 400 U/kg twice daily) alone or in combination with ETN (10 mg/kg 3 times daily), ETN alone, or vehicle (on days 13 through 19). Inflammation was assessed via changes in paw edema. Bone damage was determined by microfocal computed tomography histopathology, and immunohistochemistry. Statistical analyses were performed using a 2-way analysis of variance (ANOVA) followed by the Newman-Keuls, Dunn's, or Dunnett's multiple comparisons test or a 1-way ANOVA followed by the Dunnett's or Holm-Sidak multiple comparisons test.
Results:
RCI administration resulted in dose-dependent decreases in ankle edema and histopathologic measures of inflammation, pannus formation, cartilage damage, bone resorption, and periosteal bone formation. RCI and ETN showed combined benefits on all parameters measured. Radiographic evidence of bone damage was significantly reduced in rats that received RCI alone or in combination with ETN. This reduction in bone density loss correlated with decreases in the number of CD68-positive macrophages and cathepsin K-positive osteoclasts within the lesions.
Conclusions:
As monotherapy or adjunctive therapy with ETN, RCI attenuated CIA-induced joint structural damage in rats. These data support the clinical efficacy of RCI as adjunctive therapy for patients with RA.
... The dissected bones underwent formalin fixation and then stored in ethanol 70% [33,34,39] or washed in PBS [36]. There are however cases of in vivo measurements in anesthetized animals [14,15,28,32]. Regardless of the scan protocol used-ex vivo or in vivo-differences between the groups are observed as expected. ...
... Micro-CT provides a thorough qualitative and quantitative description of bone microarchitecture, while 3-D images can be obtained. The morphometric indexes employed by the studies of the review are summarized in Table 2. Micro-CT was performed in the tibia [28,30,32,33,36,37,40,43,50,54], the knee [29,36,39], the femur [14, 32, 35-37, 40, 42, 44, 47, 51, 52, 54], the ankle [19,29,36,39,40,50,53,54], the hind paws [15,33,34,38,40,43,45,46,48,53,54], the humerus [32] or a lumbar vertebra [19,51] ...
... Micro-CT provides a thorough qualitative and quantitative description of bone microarchitecture, while 3-D images can be obtained. The morphometric indexes employed by the studies of the review are summarized in Table 2. Micro-CT was performed in the tibia [28,30,32,33,36,37,40,43,50,54], the knee [29,36,39], the femur [14, 32, 35-37, 40, 42, 44, 47, 51, 52, 54], the ankle [19,29,36,39,40,50,53,54], the hind paws [15,33,34,38,40,43,45,46,48,53,54], the humerus [32] or a lumbar vertebra [19,51] ...
CIA is a well-studied animal model of autoimmune arthritis. It resembles rheumatoid arthritis as far as histopathological changes and molecular pathogenesis are concerned. CIA is induced by immunization with collagen type II in susceptible strains. The purpose of this review is to assess the use of CIA animal model on bone metabolism and the potential therapeutic agents that could reverse this effect. A database search from their inception to 2019 was conducted to identify experimental animal studies pertinent to CIA model and bone examination. Studies including ovariectomy or without a direct comparison between control and CIA groups were excluded. Forty-eight articles were considered suitable for inclusion. Imaging techniques, biomechanical analysis, histopathological studies, and molecular biology techniques were employed. A decrease in bone mineral density in CII arthritic animals was established. Bone loss was either periarticular, generalized or both. Although trabecular bone loss was clear, the effect on cortical bone is yet to be determined. The proposed mechanism is an imbalance between bone formation and resorption as a result of osteoclast activation. The signal pathways implicated appear to be the RANKL/RANK/OPG and the Wnt pathway. Many therapeutic targets were investigated with promising results.
... The BMD values obtained from the μCT images of the mouse maxilla ranged from 0.83 g/cm 3 to 1.55 g/cm 3 , which were considerably larger than values of the previous data, which ranged from 0.12 g/ cm 3 to 1.00 g/cm 3 for the same strain of mice, C57BL/6J mice [27][28][29][30]. This might be partly attributed to the difference in the targeted bones, which could be a key factor determining the BMD values in mice [31]. Spinal [29], tibia [28], and femoral bones [27,29,30] have been used in previous studies, while the maxillary bone was used in the present study. ...
... Histopathological analysis and magnetic resonance imaging were performed on joints of arthritic mice as described in [19]. Histological scoring was attributed to each joint section as described in [26][27][28][29]. Briefly, four histological parameters were evaluated: pannus severity, inflammatory synovium, cartilage damage and bone erosion. ...
Viruses, particularly the Epstein-Barr virus (EBV) has long been suspected to exacerbate acute arthritic symptoms. However, the cell populations that contribute to import viruses into the inflamed tissues remain to be identified. In the present study, we have investigated the role of monocytes in the transport of Murid herpesvirus 68 (MHV-68), a mouse virus closely related to EBV, using the serum transfer-induced arthritis (STIA) model. We found compelling evidence that MHV-68 infection markedly increased disease severity in NR4A1-/- mice, which are deficient for Ly6Clow monocytes. In contrast, the MHV-68-induced enhancement of joint inflammation was lessened in CCR2−/- mice, suggesting the involvement of inflammatory Ly6Chigh monocytes in viral transport. We also observed that following selective depletion of monocyte subsets by administration of clodronate, MHV-68 transport into the synovium occurs only in the presence of Ly6Chigh monocytes. Tracking of adoptively transferred Ly6Chigh GFP infected monocytes into arthritic CCR2−/− mice by two-photon intravital microscopy showed that this monocyte subset has the capacity to deliver viruses to inflamed AR joints, as confirmed by the detection of viral DNA in inflamed tissues of recipient mice. We thus conclude that Ly6Chigh monocytes import MHV-68 when they are mobilized to the inflamed arthritic joint.
