Pub Date : 2025-02-27DOI: 10.1186/s13075-025-03506-x
Shi-Yang Feng, Meng-Nan Cao, Chen-Chen Gao, Yi-Xin Li, Jie Lei, Kai-Yuan Fu
This study aimed to investigate the role and mechanism of the Akt2 pathway in different stages of anterior disc displacement (ADD)-induced temporomandibular joint osteoarthritis (TMJOA). A rat model for TMJOA that simulates anterior disc displacement was established. For inhibit Akt2 expression in subchondral bone, rats were intravenously injected with adeno-associated virus carrying Akt2 shRNA at a titer of 1 × 1012 transducing units/mL 10 days before the ADD or sham operations. The rats were euthanized and evaluated 1 or 8 weeks after surgery, as these time points represented the early or advanced stage of ADD. Immunostaining was performed to examine the expression and location of phosphorylated Akt2 in different stages of ADD. Microcomputed tomography, hematoxylin and eosin staining, toluidine blue staining, Western blotting, immunohistochemical and immunofluorescence staining were used to elucidate the pathological changes and potential mechanisms underlying ADD-induced TMJOA. In the rat model of ADD-induced TMJOA, rapid condylar bone loss occurred with increased phosphorylation of Akt2 in subchondral bone macrophages within 1 week post-surgery. At 8 weeks after surgery, abnormal remodeling of subchondral bone and degenerative changes in cartilage were observed. Inhibiting Akt2 reduced condylar bone resorption following ADD surgery while improving condylar bone morphology at 8 weeks post-surgery. Additionally, inhibition of Akt2 alleviated cartilage degeneration characterized by a decreased number of apoptotic chondrocytes, reduced expression of matrix metalloproteinases, and increased collagen type II expression in cartilage tissue. The Akt2 pathway is activated mainly in subchondral bone macrophages during the early stage of ADD and plays an important role in regulating subchondral bone remodeling. Inhibition of Akt2 could serve as a prophylactic treatment to slow the progression of ADD-induced TMJOA.
{"title":"Akt2 inhibition alleviates temporomandibular joint osteoarthritis by preventing subchondral bone loss","authors":"Shi-Yang Feng, Meng-Nan Cao, Chen-Chen Gao, Yi-Xin Li, Jie Lei, Kai-Yuan Fu","doi":"10.1186/s13075-025-03506-x","DOIUrl":"https://doi.org/10.1186/s13075-025-03506-x","url":null,"abstract":"This study aimed to investigate the role and mechanism of the Akt2 pathway in different stages of anterior disc displacement (ADD)-induced temporomandibular joint osteoarthritis (TMJOA). A rat model for TMJOA that simulates anterior disc displacement was established. For inhibit Akt2 expression in subchondral bone, rats were intravenously injected with adeno-associated virus carrying Akt2 shRNA at a titer of 1 × 1012 transducing units/mL 10 days before the ADD or sham operations. The rats were euthanized and evaluated 1 or 8 weeks after surgery, as these time points represented the early or advanced stage of ADD. Immunostaining was performed to examine the expression and location of phosphorylated Akt2 in different stages of ADD. Microcomputed tomography, hematoxylin and eosin staining, toluidine blue staining, Western blotting, immunohistochemical and immunofluorescence staining were used to elucidate the pathological changes and potential mechanisms underlying ADD-induced TMJOA. In the rat model of ADD-induced TMJOA, rapid condylar bone loss occurred with increased phosphorylation of Akt2 in subchondral bone macrophages within 1 week post-surgery. At 8 weeks after surgery, abnormal remodeling of subchondral bone and degenerative changes in cartilage were observed. Inhibiting Akt2 reduced condylar bone resorption following ADD surgery while improving condylar bone morphology at 8 weeks post-surgery. Additionally, inhibition of Akt2 alleviated cartilage degeneration characterized by a decreased number of apoptotic chondrocytes, reduced expression of matrix metalloproteinases, and increased collagen type II expression in cartilage tissue. The Akt2 pathway is activated mainly in subchondral bone macrophages during the early stage of ADD and plays an important role in regulating subchondral bone remodeling. Inhibition of Akt2 could serve as a prophylactic treatment to slow the progression of ADD-induced TMJOA.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"4 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-26DOI: 10.1186/s13075-025-03507-w
Anne-Laure Mausset-Bonnefont, Karine Toupet, Christian Jorgensen, Danièle Noël
The aim of this study was to provide an in-depth longitudinal locomotor and structural characterisation of the collagenase-induced osteoarthritis (CIOA) mouse model, using the most relevant and up-to-date non-invasive locomotor phenotyping and imaging methods. The ultimate goal of this study was to predict histological scores, the gold standard parameter in osteoarthritis (OA), based on locomotor or structural deficits. The CIOA model was induced in C57BL/6 male mice, which were then maintained in their home cage with or without a running wheel for 6 weeks. Both global and fine locomotor effects were measured using the open field and Catwalk™ tests. Imaging of bone and cartilage was performed using either µCT, contrast-enhanced µCT or confocal laser scanning microscopy (CLSM) at different time points. Correlations between functional or structural changes and histological scores were sought in order to provide tools for predicting histological degradation. Locomotor deficits were observed at early time points (days 3 to 9) but did not persist to the end of the experiment. Signs of inflammation appeared as early as day 9. They worsened on day 28 as the disease progressed and meniscal calcifications were observed by µCT. The early functional and structural changes correlated with the histological scores measured post mortem and some specific locomotor or structural parameters were identified as predictors of histological changes. Free exercise (voluntary running wheel activity) did not seem to influence the severity of the observed changes. Open-field quantification of kinetic parameters is a simple and timely relevant test to detect early locomotor changes and predict histological changes. Meniscal calcifications and osteophyte formation, which can be observed by µCT at early time points, are also highly predictive of OA severity. These two non-invasive techniques are very useful for longitudinal monitoring of mice and OA score prediction.
{"title":"Longitudinal assessment of structural and locomotor deficits as a prediction of severity in the collagenase-induced mouse model of osteoarthritis","authors":"Anne-Laure Mausset-Bonnefont, Karine Toupet, Christian Jorgensen, Danièle Noël","doi":"10.1186/s13075-025-03507-w","DOIUrl":"https://doi.org/10.1186/s13075-025-03507-w","url":null,"abstract":"The aim of this study was to provide an in-depth longitudinal locomotor and structural characterisation of the collagenase-induced osteoarthritis (CIOA) mouse model, using the most relevant and up-to-date non-invasive locomotor phenotyping and imaging methods. The ultimate goal of this study was to predict histological scores, the gold standard parameter in osteoarthritis (OA), based on locomotor or structural deficits. The CIOA model was induced in C57BL/6 male mice, which were then maintained in their home cage with or without a running wheel for 6 weeks. Both global and fine locomotor effects were measured using the open field and Catwalk™ tests. Imaging of bone and cartilage was performed using either µCT, contrast-enhanced µCT or confocal laser scanning microscopy (CLSM) at different time points. Correlations between functional or structural changes and histological scores were sought in order to provide tools for predicting histological degradation. Locomotor deficits were observed at early time points (days 3 to 9) but did not persist to the end of the experiment. Signs of inflammation appeared as early as day 9. They worsened on day 28 as the disease progressed and meniscal calcifications were observed by µCT. The early functional and structural changes correlated with the histological scores measured post mortem and some specific locomotor or structural parameters were identified as predictors of histological changes. Free exercise (voluntary running wheel activity) did not seem to influence the severity of the observed changes. Open-field quantification of kinetic parameters is a simple and timely relevant test to detect early locomotor changes and predict histological changes. Meniscal calcifications and osteophyte formation, which can be observed by µCT at early time points, are also highly predictive of OA severity. These two non-invasive techniques are very useful for longitudinal monitoring of mice and OA score prediction.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"32 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-26DOI: 10.1186/s13075-025-03512-z
Marketa Dudkova, Anna Petrackova, Martin Radvansky, Martina Skacelova, Jakub Videman, Jirina Manakova, Veronika Smotkova Kraiczova, Milos Kudelka, Andrea Smrzova, Katerina Langova, Frantisek Mrazek, Eva Kriegova, Pavel Horak
To determine differences in the blood innate gene expression signatures of systemic lupus erythematosus (SLE) patients across various organ manifestations and disease activity, with a focus on lupus nephritis (LN) and central nervous system (CNS) involvement. Toll-like receptor family (TLR 1–10) mRNA expression was investigated in peripheral blood mononuclear cells from patients with SLE (n = 74) and healthy controls (n = 34). We compared patients with histologically confirmed active LN or neuropsychiatric systemic lupus erythematosus (NPSLE) with patients without these symptoms. The expression of TLR mRNA was determined by RT‒qPCR using a high-throughput SmartChip Real-Time-qPCR system (WaferGen). Multivariate analysis and nonparametric statistics were used for data analysis to assess the associations between TLRs and disease activity and severity. TLR4 (0.044 vs. 0.081, p = 0.012) was upregulated and TLR10 (0.009 vs. 0.006, p = 0.0007) was downregulated in the whole cohort of SLE patients compared to healthy controls. A comparison of the active LN group with participants without kidney involvement revealed increased expression of TLR2 (0.078 vs. 0.03, p = 0.009), and TLR5 (0.035 vs. 0.017, p = 0.03). Moreover, a significant difference was observed in TLR9 expression between inactive LN and the control group (0.014 vs. 0.009, p = 0.01), together with borderline correlation in TLR2 expression (0.04 vs. 0.03, p = 0.06). Receiver operating characteristic (ROC) curve analysis revealed that TLR1 and TLR2 expression were the best potential diagnostic markers for active LN. The NPSLE group showed upregulation of TLR1 (0.088 vs. 0.048, p = 0.01), TLR4 (0.173 vs. 0.066, p = 0.0003) and TLR6 (0.087 vs. 0.036, 0.007). Our correlation analysis supported the close relationships among the expression of individual TLRs in the whole lupus cohort and its subgroups. Our study revealed differences in TLR expression between a lupus cohort and healthy controls. Additionally, our analysis provides insight into specific TLR expression in cases with severe organ manifestations, such as LN and NPSLE. The multiple mutual relationships of TLRs demonstrate the activation of innate immunity in SLE and suggest promising targets for future therapies or diagnostics.
{"title":"Blood gene expression of Toll-like receptors in SLE patients with lupus nephritis or neuropsychiatric systemic lupus erythematosus","authors":"Marketa Dudkova, Anna Petrackova, Martin Radvansky, Martina Skacelova, Jakub Videman, Jirina Manakova, Veronika Smotkova Kraiczova, Milos Kudelka, Andrea Smrzova, Katerina Langova, Frantisek Mrazek, Eva Kriegova, Pavel Horak","doi":"10.1186/s13075-025-03512-z","DOIUrl":"https://doi.org/10.1186/s13075-025-03512-z","url":null,"abstract":"To determine differences in the blood innate gene expression signatures of systemic lupus erythematosus (SLE) patients across various organ manifestations and disease activity, with a focus on lupus nephritis (LN) and central nervous system (CNS) involvement. Toll-like receptor family (TLR 1–10) mRNA expression was investigated in peripheral blood mononuclear cells from patients with SLE (n = 74) and healthy controls (n = 34). We compared patients with histologically confirmed active LN or neuropsychiatric systemic lupus erythematosus (NPSLE) with patients without these symptoms. The expression of TLR mRNA was determined by RT‒qPCR using a high-throughput SmartChip Real-Time-qPCR system (WaferGen). Multivariate analysis and nonparametric statistics were used for data analysis to assess the associations between TLRs and disease activity and severity. TLR4 (0.044 vs. 0.081, p = 0.012) was upregulated and TLR10 (0.009 vs. 0.006, p = 0.0007) was downregulated in the whole cohort of SLE patients compared to healthy controls. A comparison of the active LN group with participants without kidney involvement revealed increased expression of TLR2 (0.078 vs. 0.03, p = 0.009), and TLR5 (0.035 vs. 0.017, p = 0.03). Moreover, a significant difference was observed in TLR9 expression between inactive LN and the control group (0.014 vs. 0.009, p = 0.01), together with borderline correlation in TLR2 expression (0.04 vs. 0.03, p = 0.06). Receiver operating characteristic (ROC) curve analysis revealed that TLR1 and TLR2 expression were the best potential diagnostic markers for active LN. The NPSLE group showed upregulation of TLR1 (0.088 vs. 0.048, p = 0.01), TLR4 (0.173 vs. 0.066, p = 0.0003) and TLR6 (0.087 vs. 0.036, 0.007). Our correlation analysis supported the close relationships among the expression of individual TLRs in the whole lupus cohort and its subgroups. Our study revealed differences in TLR expression between a lupus cohort and healthy controls. Additionally, our analysis provides insight into specific TLR expression in cases with severe organ manifestations, such as LN and NPSLE. The multiple mutual relationships of TLRs demonstrate the activation of innate immunity in SLE and suggest promising targets for future therapies or diagnostics.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"32 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-25DOI: 10.1186/s13075-025-03474-2
Seung Hoon Lee, Kyu Hoon Lee, Dongju Kim, Chanhyeok Jeon, Min Whangbo, Hye-Ryeong Jo, Jeehee Youn, Chang-Hun Lee, Sung Hoon Choi, Ye-Soo Park, Bora Nam, Sungsin Jo, Tae-Hwan Kim
Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by ectopic bone formation. The anti-inflammatory function of dipeptidyl peptidase-4 (DPP4) inhibitor has been reported in bone metabolism, but its utility in AS has not previously been investigated. We assessed DPP4 level in serum, synovial fluid, and facet joint tissue of AS patients. Additionally, we investigated the effect of a DPP4 inhibitor in an experimental AS model using curdlan-injected SKG mice. Following curdlan injection, SKG mice were orally administered a DPP4 inhibitor three times per week for 5 weeks and observed clinical arthritis scores, and analyzed by micro-CT. Furthermore, osteoclast precursor cells (OPCs) from curdlan-injected SKG mice were treated with DPP4 inhibitor and evaluated the inhibitory effects of this treatment in vitro. Soluble DPP4 level was elevated in the serum and synovial fluid of patients with AS compared to those in the control group. Expression of DPP4 increased gradually during human osteoclastogenesis and was high in mature osteoclasts. Oral administration of a DPP4 inhibitor resulted in a decrease in thickness of the hind paw, clinical arthritis scores, and enthesitis at the ankle in curdlan-injected SKG mice compared to the vehicle group. Micro-CT data revealed a significant reduction in inflammation-induced low bone density in the DPP4 inhibitor group. Moreover, treatment with a DPP4 inhibitor significantly reduced osteoclast differentiation of OPC in addition to decreasing expression of osteoclast differentiation markers. Our findings suggest that inhibiting DPP4 may have a therapeutic effect on inflammation-mediated ectopic bone formation in AS patients.
{"title":"Targeting osteoclast-derived DPP4 alleviates inflammation-mediated ectopic bone formation in ankylosing spondylitis","authors":"Seung Hoon Lee, Kyu Hoon Lee, Dongju Kim, Chanhyeok Jeon, Min Whangbo, Hye-Ryeong Jo, Jeehee Youn, Chang-Hun Lee, Sung Hoon Choi, Ye-Soo Park, Bora Nam, Sungsin Jo, Tae-Hwan Kim","doi":"10.1186/s13075-025-03474-2","DOIUrl":"https://doi.org/10.1186/s13075-025-03474-2","url":null,"abstract":"Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by ectopic bone formation. The anti-inflammatory function of dipeptidyl peptidase-4 (DPP4) inhibitor has been reported in bone metabolism, but its utility in AS has not previously been investigated. We assessed DPP4 level in serum, synovial fluid, and facet joint tissue of AS patients. Additionally, we investigated the effect of a DPP4 inhibitor in an experimental AS model using curdlan-injected SKG mice. Following curdlan injection, SKG mice were orally administered a DPP4 inhibitor three times per week for 5 weeks and observed clinical arthritis scores, and analyzed by micro-CT. Furthermore, osteoclast precursor cells (OPCs) from curdlan-injected SKG mice were treated with DPP4 inhibitor and evaluated the inhibitory effects of this treatment in vitro. Soluble DPP4 level was elevated in the serum and synovial fluid of patients with AS compared to those in the control group. Expression of DPP4 increased gradually during human osteoclastogenesis and was high in mature osteoclasts. Oral administration of a DPP4 inhibitor resulted in a decrease in thickness of the hind paw, clinical arthritis scores, and enthesitis at the ankle in curdlan-injected SKG mice compared to the vehicle group. Micro-CT data revealed a significant reduction in inflammation-induced low bone density in the DPP4 inhibitor group. Moreover, treatment with a DPP4 inhibitor significantly reduced osteoclast differentiation of OPC in addition to decreasing expression of osteoclast differentiation markers. Our findings suggest that inhibiting DPP4 may have a therapeutic effect on inflammation-mediated ectopic bone formation in AS patients.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"6 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-24DOI: 10.1186/s13075-025-03490-2
Jingchun Wu, Ruiling Feng, Ruoyi Wang, Jing He
Primary Sjogren’s Syndrome (pSS) is a systemic autoimmune disorder characterized by lymphocyte infiltration of the exocrine glands. Disease duration plays a pivotal role in evaluating the development of SS. In this study, we aimed to clarify the clinical manifestations of pSS across various stages of its progression, thereby offering critical insights for early diagnosis and targeted management strategies for Sjogren’s Syndrome. We conducted a retrospective analysis involving 3,978 patients with primary Sjogren’s Syndrome (mean [SD] age: 53.1[24] years) from Peking University People’s Hospital between January 2015 and December 2022. We classified patients into five distinct groups based on the duration of the syndrome: T0 (≤ 1 year), T1 (> 1 year, ≤ 5 years), T2 (> 5 years, ≤ 10 years), T3 (> 10 years, ≤ 20 years), and T4 (> 20 years). We observed a statistically significant increase in the percentage of pSS patients with white blood cell (WBC) decrease, specifically: T0 (9.23%), T1 (15.40%), T2 (22.62%), T3 (20.22%), T4 (26.45%). The decreases in hemoglobin (HGB) and platelet (PLT) were also robustly associated with extended disease duration (p < 0.0001). Simultaneously, systemic involvements aggravated with disease progression as incidence rates of skin, joint, lung, and nervous system were strikingly increased in each group. The findings also indicated that patients with long-term pSS exhibit a higher likelihood of developing comorbid conditions, such as diabetes and tumors. In summary, disease duration serves as a crucial determinant for the prognosis of patients with pSS. Therefore, early identification of symptoms and initiation of therapies are imperative for mitigating the risk of significant complications in pSS patients.
{"title":"Impact of disease duration on systemic clinical profile in Sjogren’s syndrome","authors":"Jingchun Wu, Ruiling Feng, Ruoyi Wang, Jing He","doi":"10.1186/s13075-025-03490-2","DOIUrl":"https://doi.org/10.1186/s13075-025-03490-2","url":null,"abstract":"Primary Sjogren’s Syndrome (pSS) is a systemic autoimmune disorder characterized by lymphocyte infiltration of the exocrine glands. Disease duration plays a pivotal role in evaluating the development of SS. In this study, we aimed to clarify the clinical manifestations of pSS across various stages of its progression, thereby offering critical insights for early diagnosis and targeted management strategies for Sjogren’s Syndrome. We conducted a retrospective analysis involving 3,978 patients with primary Sjogren’s Syndrome (mean [SD] age: 53.1[24] years) from Peking University People’s Hospital between January 2015 and December 2022. We classified patients into five distinct groups based on the duration of the syndrome: T0 (≤ 1 year), T1 (> 1 year, ≤ 5 years), T2 (> 5 years, ≤ 10 years), T3 (> 10 years, ≤ 20 years), and T4 (> 20 years). We observed a statistically significant increase in the percentage of pSS patients with white blood cell (WBC) decrease, specifically: T0 (9.23%), T1 (15.40%), T2 (22.62%), T3 (20.22%), T4 (26.45%). The decreases in hemoglobin (HGB) and platelet (PLT) were also robustly associated with extended disease duration (p < 0.0001). Simultaneously, systemic involvements aggravated with disease progression as incidence rates of skin, joint, lung, and nervous system were strikingly increased in each group. The findings also indicated that patients with long-term pSS exhibit a higher likelihood of developing comorbid conditions, such as diabetes and tumors. In summary, disease duration serves as a crucial determinant for the prognosis of patients with pSS. Therefore, early identification of symptoms and initiation of therapies are imperative for mitigating the risk of significant complications in pSS patients.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"25 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Axial spondyloarthritis (axSpA) is an inflammatory rheumatic disease with challenges in diagnosis and disease activity assessment. While alterations in immunoglobulin G (IgG) N-glycosylation have been observed in varied rheumatic diseases, those in axSpA remains unclear. This study aims to explore the role of IgG N-glycan profiles in diagnosis and disease activity of axSpA. A clinical case-control study was conducted involving patients with axSpA (n = 138), systemic lupus erythematosus (n = 102), rheumatoid arthritis (n = 106), osteoarthritis (n = 33), gout (n = 41) and healthy controls (n = 117). Ultra-performance liquid chromatography was employed to analyze the composition of the serum IgG N-glycome. Associations between IgG N-glycans and axSpA were investigated and compared to healthy controls and other four rheumatic diseases. The relationship among IgG N-glycosylation, disease activity, and inflammatory cytokines of axSpA patients were analyzed. The receiver operating characteristic (ROC) curve analysis was applied to evaluate the diagnostic/classification performance of IgG N-glycans to distinguish axSpA and its disease activity. In patients with axSpA, the abundances of IgG galactosylation and sialylation were significantly lower than healthy controls, while the abundance of fucosylation was higher than the other four studied rheumatic diseases. Additionally, two asialylated IgG N-glycans (FA2 and FA2 [3]G1) were associated with axSpA, with adjusted odds ratios (AORs) of 5.62 (95% CI: 3.41–9.24) and 0.33 (95% CI: 0.22–0.50), respectively. Notably, decreased FA2 [3]G1 emerged as a characteristic IgG N-glycan associated with all five studied rheumatic diseases, while decreased FA2BG2S2 was a unique IgG N-glycan differentiating axSpA from the other four rheumatic diseases. Furthermore, FA2 displayed positive association with disease activity indicators (ASDAS-CRP, SPARCC-SIJ and SPARCC-spine) in axSpA. IgG N-glycans, particularly FA2 [3]G1, FA2BG2S2 and FA2, demonstrated canonical correlation with inflammatory cytokines, including interleukin-23 and tumor necrosis factor α, in axSpA (r = 0.519, P = 0.017). Specific IgG N-glycans hold potential as novel biomarkers to enhance diagnosis and disease activity assessment in axSpA management.
{"title":"Profiling of IgG N-glycosylation for axial spondyloarthritis and other rheumatic diseases","authors":"Xiaojia Xu, Zhixian Chen, Manshu Song, Zhiduo Hou, Lois Balmer, Chunbin Zhou, Yayi Huang, Haifeng Hou, Wei Wang, Ling Lin","doi":"10.1186/s13075-025-03505-y","DOIUrl":"https://doi.org/10.1186/s13075-025-03505-y","url":null,"abstract":"Axial spondyloarthritis (axSpA) is an inflammatory rheumatic disease with challenges in diagnosis and disease activity assessment. While alterations in immunoglobulin G (IgG) N-glycosylation have been observed in varied rheumatic diseases, those in axSpA remains unclear. This study aims to explore the role of IgG N-glycan profiles in diagnosis and disease activity of axSpA. A clinical case-control study was conducted involving patients with axSpA (n = 138), systemic lupus erythematosus (n = 102), rheumatoid arthritis (n = 106), osteoarthritis (n = 33), gout (n = 41) and healthy controls (n = 117). Ultra-performance liquid chromatography was employed to analyze the composition of the serum IgG N-glycome. Associations between IgG N-glycans and axSpA were investigated and compared to healthy controls and other four rheumatic diseases. The relationship among IgG N-glycosylation, disease activity, and inflammatory cytokines of axSpA patients were analyzed. The receiver operating characteristic (ROC) curve analysis was applied to evaluate the diagnostic/classification performance of IgG N-glycans to distinguish axSpA and its disease activity. In patients with axSpA, the abundances of IgG galactosylation and sialylation were significantly lower than healthy controls, while the abundance of fucosylation was higher than the other four studied rheumatic diseases. Additionally, two asialylated IgG N-glycans (FA2 and FA2 [3]G1) were associated with axSpA, with adjusted odds ratios (AORs) of 5.62 (95% CI: 3.41–9.24) and 0.33 (95% CI: 0.22–0.50), respectively. Notably, decreased FA2 [3]G1 emerged as a characteristic IgG N-glycan associated with all five studied rheumatic diseases, while decreased FA2BG2S2 was a unique IgG N-glycan differentiating axSpA from the other four rheumatic diseases. Furthermore, FA2 displayed positive association with disease activity indicators (ASDAS-CRP, SPARCC-SIJ and SPARCC-spine) in axSpA. IgG N-glycans, particularly FA2 [3]G1, FA2BG2S2 and FA2, demonstrated canonical correlation with inflammatory cytokines, including interleukin-23 and tumor necrosis factor α, in axSpA (r = 0.519, P = 0.017). Specific IgG N-glycans hold potential as novel biomarkers to enhance diagnosis and disease activity assessment in axSpA management.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"25 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-22DOI: 10.1186/s13075-025-03504-z
Felix Kurt Seese, Pia Roscher, Birte Coppers, Julia Greenfield, Manuel Grahammer, Sebastian Kuhn, Latika Gupta, Georg Schett, Johannes Knitza, Anna-Maria Liphardt
Manual muscle testing (MMT8), the current gold standard for assessing muscle function in patients with idiopathic inflammatory myopathies (IIM), has notable limitations. This study had three aims (1) to compare MMT8 with inertial sensor-based gait analysis, (2) to evaluate patient-performed functional tests guided by shared decision-making (SDM), and (3) to investigate adherence to electronic patient-reported outcomes (ePROs). Gold standard muscle function assessment (MMT8) was performed at baseline (T0) and three months (T1). Additionally, inertial-sensor-based gait analysis was completed at T0 and two standardized upper extremity (Modified Barré test; 10-time arm lift test) and two lower extremity muscle endurance tests (60-second Sit-to-Stand (STS) test; Mingazzini test) were presented to patients to choose from. Through shared decision-making, each patient selected one test for lower and upper extremities and opted to record weekly results on paper or through a medical app. Correlations between gait parameters, functional tests, and MMT8 were analyzed, while agreement between patient- and healthcare professional (HCP)-recorded results at T0 and T1 was assessed. Responsiveness to change was also evaluated. A total of 28 IIM patients (67.9% female; mean age 57.4 ± 12.9 years) were enrolled. Moderate correlations were observed between gait parameters and MMT8, such as walking speed (r = 0.545, p = 0.004) and stride length (r = 0.580, p = 0.002). All patients selected the Modified Barré test for assessing upper extremity function and 60.7% of patients chose the Mingazzini test for lower extremity function. Agreement between patient- and HCP-recorded functional test results was excellent at baseline and after three months (ICC 0.99–1.00). Functional tests demonstrated strong correlations with MMT8, particularly for the Mingazzini test (r = 0.762, p = 0.002). Patients preferred app-based recording (82.1%) over paper-based methods and weekly ePROs were completed on average 6.9 out of 12 weeks (57.5%). Patient-performed functional tests are reliable, scalable alternatives to MMT8, with gait analysis providing complementary insights. Digitally supported self-assessments can enhance clinical workflows, remote monitoring, and treat-to-target strategies, empowering patients and improving disease management.
{"title":"Toward digitally supported self-assessment of patients with idiopathic inflammatory myopathies","authors":"Felix Kurt Seese, Pia Roscher, Birte Coppers, Julia Greenfield, Manuel Grahammer, Sebastian Kuhn, Latika Gupta, Georg Schett, Johannes Knitza, Anna-Maria Liphardt","doi":"10.1186/s13075-025-03504-z","DOIUrl":"https://doi.org/10.1186/s13075-025-03504-z","url":null,"abstract":"Manual muscle testing (MMT8), the current gold standard for assessing muscle function in patients with idiopathic inflammatory myopathies (IIM), has notable limitations. This study had three aims (1) to compare MMT8 with inertial sensor-based gait analysis, (2) to evaluate patient-performed functional tests guided by shared decision-making (SDM), and (3) to investigate adherence to electronic patient-reported outcomes (ePROs). Gold standard muscle function assessment (MMT8) was performed at baseline (T0) and three months (T1). Additionally, inertial-sensor-based gait analysis was completed at T0 and two standardized upper extremity (Modified Barré test; 10-time arm lift test) and two lower extremity muscle endurance tests (60-second Sit-to-Stand (STS) test; Mingazzini test) were presented to patients to choose from. Through shared decision-making, each patient selected one test for lower and upper extremities and opted to record weekly results on paper or through a medical app. Correlations between gait parameters, functional tests, and MMT8 were analyzed, while agreement between patient- and healthcare professional (HCP)-recorded results at T0 and T1 was assessed. Responsiveness to change was also evaluated. A total of 28 IIM patients (67.9% female; mean age 57.4 ± 12.9 years) were enrolled. Moderate correlations were observed between gait parameters and MMT8, such as walking speed (r = 0.545, p = 0.004) and stride length (r = 0.580, p = 0.002). All patients selected the Modified Barré test for assessing upper extremity function and 60.7% of patients chose the Mingazzini test for lower extremity function. Agreement between patient- and HCP-recorded functional test results was excellent at baseline and after three months (ICC 0.99–1.00). Functional tests demonstrated strong correlations with MMT8, particularly for the Mingazzini test (r = 0.762, p = 0.002). Patients preferred app-based recording (82.1%) over paper-based methods and weekly ePROs were completed on average 6.9 out of 12 weeks (57.5%). Patient-performed functional tests are reliable, scalable alternatives to MMT8, with gait analysis providing complementary insights. Digitally supported self-assessments can enhance clinical workflows, remote monitoring, and treat-to-target strategies, empowering patients and improving disease management.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"23 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-21DOI: 10.1186/s13075-025-03501-2
Negar Asgari, Ezzat Allah Ghaemi, Samaneh Tavasoli, Mehrdad Aghaei, Hadi Razavi Nikoo, Samin Zamani
Mycobacterium avium subspecies Paratuberculosis (MAP) is a bacterium known to cause Johne’s disease in ruminants and has been implicated in several autoimmune diseases. This study aimed to investigate the potential association between MAP infection and Rheumatoid Arthritis (RA). A total of 119 patients with RA and 120 healthy controls (HCs) were enrolled in the study. The participants were outpatient attendees at a rheumatology specialist’s clinic, selected according to the 2010 ACR/EULAR Classification Criteria for RA. Their serum samples were analyzed for antibodies against two peptides, MAP_402718–32 and IRF5424-434, using an indirect enzyme-linked immunosorbent assay (ELISA). A significant difference was found in the levels of anti-MAP antibodies between RA patients and HCs. RA patients were more likely to have anti-MAP_402718–32 antibodies (44.5%) vs. 10.8% in HCs. Among RA patients, treatment group patients had more antibodies (51.6%) against MAP_402718–32 than no-treatment group patients (36.4%), but this difference was not statistically significant. The antigen IRF5424-434 showed the highest antibody seroreactivity, being present in a higher percentage of RA patients (60.5%) compared to HCs (8.3%). This difference was statistically significant. There was a moderate correlation between IRF5424-434 and its MAP_402718-32 homolog. The study findings suggest that anti-MAP antibodies are more prevalent in RA patients compared to healthy controls, potentially implicating MAP in the development of RA. The strong immunological response to the antigen IRF5424-434 warrants further investigation. Although the difference in antibody levels between previously diagnosed and newly diagnosed RA patients was not statistically significant, the overall higher prevalence of these antibodies in the RA cohort supports the hypothesis of MAP’s involvement.
{"title":"Exploring the association between Mycobacterium avium subspecies paratuberculosis infection and rheumatoid arthritis: an immunological perspective","authors":"Negar Asgari, Ezzat Allah Ghaemi, Samaneh Tavasoli, Mehrdad Aghaei, Hadi Razavi Nikoo, Samin Zamani","doi":"10.1186/s13075-025-03501-2","DOIUrl":"https://doi.org/10.1186/s13075-025-03501-2","url":null,"abstract":"Mycobacterium avium subspecies Paratuberculosis (MAP) is a bacterium known to cause Johne’s disease in ruminants and has been implicated in several autoimmune diseases. This study aimed to investigate the potential association between MAP infection and Rheumatoid Arthritis (RA). A total of 119 patients with RA and 120 healthy controls (HCs) were enrolled in the study. The participants were outpatient attendees at a rheumatology specialist’s clinic, selected according to the 2010 ACR/EULAR Classification Criteria for RA. Their serum samples were analyzed for antibodies against two peptides, MAP_402718–32 and IRF5424-434, using an indirect enzyme-linked immunosorbent assay (ELISA). A significant difference was found in the levels of anti-MAP antibodies between RA patients and HCs. RA patients were more likely to have anti-MAP_402718–32 antibodies (44.5%) vs. 10.8% in HCs. Among RA patients, treatment group patients had more antibodies (51.6%) against MAP_402718–32 than no-treatment group patients (36.4%), but this difference was not statistically significant. The antigen IRF5424-434 showed the highest antibody seroreactivity, being present in a higher percentage of RA patients (60.5%) compared to HCs (8.3%). This difference was statistically significant. There was a moderate correlation between IRF5424-434 and its MAP_402718-32 homolog. The study findings suggest that anti-MAP antibodies are more prevalent in RA patients compared to healthy controls, potentially implicating MAP in the development of RA. The strong immunological response to the antigen IRF5424-434 warrants further investigation. Although the difference in antibody levels between previously diagnosed and newly diagnosed RA patients was not statistically significant, the overall higher prevalence of these antibodies in the RA cohort supports the hypothesis of MAP’s involvement.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"16 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-19DOI: 10.1186/s13075-025-03500-3
Beatriz H. Ferreira, Carolina Mazeda, Eduardo Dourado, João L. Simões, Ana Rita Prata, Rafael J. Argüello, Iola F. Duarte, Philippe Pierre, Catarina R. Almeida
Plasmacytoid dendritic cells (pDCs) play a key role in systemic sclerosis (SSc) pathophysiology. However, despite the recognised importance of metabolic reprogramming for pDC function, their metabolic profile in SSc remains to be elucidated. Thus, our study aimed to explore the metabolic profile of pDCs in SSc and their potential contribution to the disease. Peripheral blood mononuclear cells (PBMCs) were isolated from the blood of healthy donors and SSc patients. SCENITH™, a single-cell flow cytometry-based method, was applied to infer the metabolic profile of circulating pDCs from patients with SSc. pDCs (CD304+ Lin−) at steady-state or stimulated with CpG A were analysed. Toll-like receptor (TLR)9 activation was confirmed by ribosomal protein S6 phosphorylation. Circulating pDCs from ten healthy donors and fourteen SSc patients were analysed. pDCs from anti-centromere antibody-positive (ACA+) patients displayed higher mitochondrial dependence and lower glycolytic capacity than those from anti-topoisomerase I antibody-positive (ATA+) patients. Furthermore, cells from both ACA+ patients and limited cutaneous SSc (lcSSc) patients showed a stronger response towards TLR9 activation than cells from ATA+, anti-RNA polymerase III antibody-positive (ARA+) or diffuse cutaneous SSc (dcSSc) patients. An innovative single cell flow cytometry-based methodology was applied to analyse the metabolic profile of pDCs from SSc patients. Our results suggest that pDCs from ACA+ patients rely more on oxidative phosphorylation (OXPHOS) and are more responsive to external stimuli, whereas pDCs from ATA+ patients may exhibit a more activated or exhausted profile.
{"title":"Distinct metabolic profiles of circulating plasmacytoid dendritic cells in systemic sclerosis patients stratified by clinical phenotypes","authors":"Beatriz H. Ferreira, Carolina Mazeda, Eduardo Dourado, João L. Simões, Ana Rita Prata, Rafael J. Argüello, Iola F. Duarte, Philippe Pierre, Catarina R. Almeida","doi":"10.1186/s13075-025-03500-3","DOIUrl":"https://doi.org/10.1186/s13075-025-03500-3","url":null,"abstract":"Plasmacytoid dendritic cells (pDCs) play a key role in systemic sclerosis (SSc) pathophysiology. However, despite the recognised importance of metabolic reprogramming for pDC function, their metabolic profile in SSc remains to be elucidated. Thus, our study aimed to explore the metabolic profile of pDCs in SSc and their potential contribution to the disease. Peripheral blood mononuclear cells (PBMCs) were isolated from the blood of healthy donors and SSc patients. SCENITH™, a single-cell flow cytometry-based method, was applied to infer the metabolic profile of circulating pDCs from patients with SSc. pDCs (CD304+ Lin−) at steady-state or stimulated with CpG A were analysed. Toll-like receptor (TLR)9 activation was confirmed by ribosomal protein S6 phosphorylation. Circulating pDCs from ten healthy donors and fourteen SSc patients were analysed. pDCs from anti-centromere antibody-positive (ACA+) patients displayed higher mitochondrial dependence and lower glycolytic capacity than those from anti-topoisomerase I antibody-positive (ATA+) patients. Furthermore, cells from both ACA+ patients and limited cutaneous SSc (lcSSc) patients showed a stronger response towards TLR9 activation than cells from ATA+, anti-RNA polymerase III antibody-positive (ARA+) or diffuse cutaneous SSc (dcSSc) patients. An innovative single cell flow cytometry-based methodology was applied to analyse the metabolic profile of pDCs from SSc patients. Our results suggest that pDCs from ACA+ patients rely more on oxidative phosphorylation (OXPHOS) and are more responsive to external stimuli, whereas pDCs from ATA+ patients may exhibit a more activated or exhausted profile.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"29 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-15DOI: 10.1186/s13075-025-03502-1
Xinyu Wang, Lin Sun, Zhuo An, Changhong Li, Jinxia Zhao
Rheumatoid arthritis (RA) with anti-citrullinated protein/peptide antibodies (ACPA + RA) demonstrates more significant radiographic damage compared to ACPA-negative RA (ACPA- RA). Chemokine-activated signaling pathways contribute to the regulation of the bone formation and resorption. The potential role of C-X-C motif chemokine ligand 7 (CXCL7) in bone erosion and its viability as a therapeutic target for RA merit further investigation. Plasma CXCL7 concentration was quantified using enzyme-linked immunosorbent assay (ELISA). The effect of CXCL7 on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogeneis was assessed through tartrate-resistant acid phosphates (TRAP) staining and F-actin ring immunofluorescence. Western blotting analysis was used to identify the signaling pathways activated by CXCL7. To investigate the potential therapeutic effect by targeting Cxcl7, Cxcl7 neutralizing antibodies were administrated intraperitoneally to mice with collagen-induced arthritis (CIA). Histopathology and micro-computed tomography (micro-CT) scanning were utilized to assess joint inflammation and bone destruction in CIA mice. The plasma CXCL7 concentration was significantly higher in ACPA + RA compared with ACPA- RA and healthy controls. The level of CXCL7 was positively correlated with disease activity and bone erosion in RA patients. It was discovered that CXCL7 promoted RANKL-induced osteoclastogenesis in CD14 + monocytes derived from RA patients. Mechanistically, the addition of Cxcl7 significantly enhanced RANKL-induced phosphorylation of ERK1/2 and NFATc1 expresssion. Cxcl7 neutralizing antibody alleviated arthritis severity in CIA by reducing the inflammatory response, osteoclasts numbers, and bone destruction in CIA mice joints. CXCL7 contributes to the bone erosion in RA by enhancing RANKL-induced osteoclastogenesis via the activation of ERK/NFATc1 signaling pathways. CXCL7 could potentially be targeted for therapeutic interventions in RA.
{"title":"CXCL7 enhances RANKL-induced osteoclastogenesis via the activation of ERK/NFATc1 signaling pathway in inflammatory arthritis","authors":"Xinyu Wang, Lin Sun, Zhuo An, Changhong Li, Jinxia Zhao","doi":"10.1186/s13075-025-03502-1","DOIUrl":"https://doi.org/10.1186/s13075-025-03502-1","url":null,"abstract":"Rheumatoid arthritis (RA) with anti-citrullinated protein/peptide antibodies (ACPA + RA) demonstrates more significant radiographic damage compared to ACPA-negative RA (ACPA- RA). Chemokine-activated signaling pathways contribute to the regulation of the bone formation and resorption. The potential role of C-X-C motif chemokine ligand 7 (CXCL7) in bone erosion and its viability as a therapeutic target for RA merit further investigation. Plasma CXCL7 concentration was quantified using enzyme-linked immunosorbent assay (ELISA). The effect of CXCL7 on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogeneis was assessed through tartrate-resistant acid phosphates (TRAP) staining and F-actin ring immunofluorescence. Western blotting analysis was used to identify the signaling pathways activated by CXCL7. To investigate the potential therapeutic effect by targeting Cxcl7, Cxcl7 neutralizing antibodies were administrated intraperitoneally to mice with collagen-induced arthritis (CIA). Histopathology and micro-computed tomography (micro-CT) scanning were utilized to assess joint inflammation and bone destruction in CIA mice. The plasma CXCL7 concentration was significantly higher in ACPA + RA compared with ACPA- RA and healthy controls. The level of CXCL7 was positively correlated with disease activity and bone erosion in RA patients. It was discovered that CXCL7 promoted RANKL-induced osteoclastogenesis in CD14 + monocytes derived from RA patients. Mechanistically, the addition of Cxcl7 significantly enhanced RANKL-induced phosphorylation of ERK1/2 and NFATc1 expresssion. Cxcl7 neutralizing antibody alleviated arthritis severity in CIA by reducing the inflammatory response, osteoclasts numbers, and bone destruction in CIA mice joints. CXCL7 contributes to the bone erosion in RA by enhancing RANKL-induced osteoclastogenesis via the activation of ERK/NFATc1 signaling pathways. CXCL7 could potentially be targeted for therapeutic interventions in RA.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"29 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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