Driving β2- While Suppressing α-Adrenergic Receptor Activity Suppresses Joint Pathology in Inflammatory Arthritis

ObjectiveHypersympathetic activity is prominent in rheumatoid arthritis, and major life stressors precede onset in ~80% of patients. These findings and others support a link between stress, the sympathetic nervous system and disease onset and progression. Here, we extend previous research by evaluating how selective peripherally acting α/β2-adrenergic drugs affect joint destruction in adjuvant-induced arthritis.MethodsComplete Freund’s adjuvant induced inflammatory arthritis in male Lewis rats. Controls received no treatment. Arthritic rats then received vehicle or twice-daily treatment with the α-adrenergic antagonist, phentolamine (0.5 mg/day) and the β2-adrenergic agonist, terbutaline (1200 µg/day, collectively named SH1293) from day (D) of disease onset (D12) through acute (D21) and severe disease (D28). Disease progression was assessed in the hind limbs using dorsoplantar widths, X-ray analysis, micro-computed tomography, and routine histology on D14, D21, and D28 post-immunization.ResultsOn D21, SH1293 significantly attenuated arthritis in the hind limbs, based on reduced lymphocytic infiltration, preservation of cartilage, and bone volume. Pannus formation and sympathetic nerve loss were not affected by SH1293. Bone area and osteoclast number revealed high- and low-treatment-responding groups. In high-responding rats, treatment with SH1293 significantly preserved bone area and decreased osteoclast number, data that correlated with drug-mediated joint preservation. SH1293 suppressed abnormal bone formation based on reduced production of osteophytes. On D28, the arthritic sparing effects of SH1293 on lymphocytic infiltration, cartilage and bone sparing were maintained at the expense of bone marrow adipocity. However, sympathetic nerves were retracted from the talocrural joint.Conclusion and SignificanceOur findings support a significant delay in early arthritis progression by treatment with SH1293. Targeting sympathetic neurotransmission may provide a strategy to slow disease progression.

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Inhibition of Notch signalling ameliorates experimental inflammatory arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2013-203467 ◽

2013 ◽

Vol 74 (1) ◽

pp. 267-274 ◽

Cited By ~ 41

Author(s):

Jong-Sung Park ◽

Seol-Hee Kim ◽

Kwangmeyung Kim ◽

Cheng-Hao Jin ◽

Ki Young Choi ◽

...

Keyword(s):

Proinflammatory Cytokines ◽

Inflammatory Arthritis ◽

Near Infrared ◽

Joint Destruction ◽

Disease Onset ◽

Disease Process ◽

Neutrophil Infiltration ◽

Notch Signalling ◽

Pharmacological Inhibition

ObjectiveTo test the hypothesis that Notch signalling plays a role in the pathogenesis of rheumatoid arthritis (RA) and to determine whether pharmacological inhibition of Notch signalling with γ-secretase inhibitors can ameliorate the RA disease process in an animal model.MethodsCollagen-induced arthritis was induced in C57BL/6 or Notch antisense transgenic mice by immunisation with chicken type II collagen (CII). C57BL/6 mice were administered with different doses of inhibitors of γ-secretase, an enzyme required for Notch activation, at disease onset or after onset of symptoms. Severity of arthritis was monitored by clinical and histological scores, and in vivo non-invasive near-infrared fluorescence (NIRF) images. Micro-CT was used to confirm joint destruction. The levels of CII antibodies and cytokines in serum were determined by ELISA and bead-based cytokine assay. The expression levels of cytokines were studied by quantitative PCR in rheumatoid synovial fibroblasts.ResultsThe data show that Notch signalling stimulates synoviocytes and accelerates their production of proinflammatory cytokines and immune responses involving the upregulation of IgG1 and IgG2a. Pharmacological inhibition of γ-secretase and antisense-mediated knockdown of Notch attenuates the severity of inflammatory arthritis, including arthritis indices, paw thickness, tissue damage and neutrophil infiltration, and reduces the levels of active NF-κB, ICAM-1, proinflammatory cytokines and matrix metalloproteinase-3 activity in the mouse model of RA.ConclusionsThese results suggest that Notch is involved in the pathogenesis of RA and that inhibition of Notch signalling is a novel approach for treating RA.

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OP0036 IL-6 ACTIVATES YES-ASSOCIATED PROTEIN (YAP) IN FIBROBLASTS AND INDUCES YAP-SNAIL COMPLEX FORMATION TO DRIVE SYNOVIAL LINING PATHOLOGY IN INFLAMMATORY ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2530 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 19.1-19

Author(s):

R. Symons ◽

F. Colella ◽

F. Collins ◽

A. Roelofs ◽

C. De Bari

Keyword(s):

Transcription Factor ◽

Complex Formation ◽

Inflammatory Arthritis ◽

Normal Mouse ◽

Joint Destruction ◽

Proximity Ligation Assay ◽

Synovial Lining ◽

Arthritis Severity ◽

Marginal Erosions

Background:In rheumatoid arthritis (RA), the fibroblast-like synoviocytes (FLS) in synovial lining become invasive and cause joint destruction. The molecular mechanisms underpinning this pathogenic FLS phenotype are incompletely understood. The FLS descend from Growth differentiation factor 5 (Gdf5)-expressing joint interzone cells in the embryo, and we showed that conditional ablation of the transcriptional co-activator Yes associated protein (Yap) in Gdf5-lineage cells prevents synovial lining hyperplasia after traumatic cartilage injury in mice [1].Objectives:Here, we investigated a potential role for Yap in pathogenic FLS in immune-mediated inflammatory arthritis.Methods:Immunohistochemistry was used to detect Yap in human RA synovium and Yap, Snail and Ctgf in mouse synovium following antigen-induced arthritis (AIA). To determine the effect of Yap knockout (KO) in synovial stromal cells, AIA was induced in Gdf5-Cre;tdTomato;Yapfl/fl (Yap cKO) and Gdf5-Cre;tdTomato;Yapwt/wt (control) mice, or in Pdgfrα-CreER;Yapfl/fl (Yap ciKO, targeting Pdgfrα-expressing fibroblasts) and Yapfl/fl or YapWT/fl (control) mice after adult tamoxifen induction. Yap KO in both models was confirmed by immunohistochemistry. After nine days, arthritis severity was determined by histological scoring of synovial lining hyperplasia, immune infiltrates, cellular exudate, and marginal erosions. TdTomato+ Gdf5-lineage cells in synovium were quantified. In vitro, Yap reporter cells were treated with inflammatory cytokines to evaluate their ability to stimulate Yap-induced GFP expression by flow cytometry. Snail overexpression, siRNA-mediated Yap knockdown, and IL-6/sIL-6R stimulation were performed on normal mouse FLS, AIA-FLS or human RA-FLS, and cell invasion through a matrigel-coated transwell was quantified. A proximity ligation assay was utilised to detect Yap/Snail complex formation.Results:Average expression levels of Yap (p<0.0001), its transcription factor partner Snail (p=0.002), and their downstream target Ctgf (p=0.0003), were increased in mouse synovium after AIA (n=5), and Yap was highly expressed by FLS in human RA synovium. Yap cKO mice (n=24) showed a significantly decreased arthritis severity (p=0.002) after AIA compared to controls (n=22), with significant reductions in synovial lining hyperplasia (p<0.001), synovial immune cell infiltrates (p=0.026) and marginal erosions (p=0.002). Similarly, Yap ciKO mice (n=6) showed a significant decrease in arthritis score (p=0.039) after AIA compared to controls (n=9). However, both control mice (p<0.001) and Yap cKO mice (p<0.001) showed an extensive expansion of tdTomato+ Gdf5-lineage synovial cells after AIA, with no significant difference between control and Yap cKO mice. In vitro, Yap knockdown prevented IL-6/sIL-6R-induced invasion of normal mouse FLS (p=0.037) and decreased the invasiveness of AIA-FLS (p=0.0057). Using Yap reporter cells, we found that Yap was activated by IL-6/sIL-6R (p=0.016), but not TNFα or IL-1β. Finally, IL-6/sIL-6R treatment of normal mouse FLS (p=0.033) or human RA-FLS (p=0.036) induced Yap-Snail complex formation, and Yap knockdown prevented FLS invasion induced by Snail overexpression (p=0.027).Conclusion:These data demonstrate that via activation by IL-6, and co-operation with the transcription factor Snail, Yap acts as a key modulator of the invasive and destructive phenotype of FLS in inflammatory arthritis. Therapeutic targeting of Yap could reduce joint destruction in RA.References:[1]A. J. Roelofs et al., “Joint morphogenetic cells in the adult mammalian synovium,” Nat. Commun., vol. 8, no. May, p. 15040, 2017. DOI: 10.1136/annrheumdis-2018-213799Acknowledgements:This work was funded by the Medical Research Council (MR/L020211/1 and MR/L022893/1) and Versus Arthritis (20775 and 21156).Disclosure of Interests:None declared

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Writers Are Common among Parkinson’s Disease Patients: A Longitudinal Study

Behavioural Neurology ◽

10.1155/2021/5559926 ◽

2021 ◽

Vol 2021 ◽

pp. 1-3

Author(s):

Anna Aasly ◽

Jan O. Aasly

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Longitudinal Study ◽

General Population ◽

Personality Disorders ◽

Disease Progression ◽

Medical Record ◽

Disease Onset ◽

Psychological Characteristics ◽

Personality Profile

Parkinson’s disease (PD) patients may have a specific personality profile, which includes being introvert, cautious and devoted to hard work. The evaluation of psychological characteristics must be evaluated according to methods for assessments of personality disorders. Such evaluations are often time-consuming and available only in research settings. The “parkinsonian trait” may be established early in life but may change with disease progression. To overcome this long interval before onset of PD questions on literary activities were included in the medical record. Three percent of PD patients could be defined as writers, significantly higher than observed in the general population. PD writers published their first books long before onset of disease. Being a writer is an extrovert trait meaning that the patient is prepared for criticism and publicity. We suggest that questions regarding personal activities prior to disease onset add valuable information on personality which differs significantly from traits observed later in the disease period.

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Progression and prognosis in multiple system atrophy presenting with REM behavior disorder

Neurology ◽

10.1212/wnl.0000000000009372 ◽

2020 ◽

Vol 94 (17) ◽

pp. e1828-e1834 ◽

Cited By ~ 4

Author(s):

Giulia Giannini ◽

Vincenzo Mastrangelo ◽

Federica Provini ◽

Andrea Droghini ◽

Annagrazia Cecere ◽

...

Keyword(s):

Multiple System Atrophy ◽

Disease Progression ◽

Survival Data ◽

Disease Onset ◽

Rem Sleep Behavior Disorder ◽

Behavior Disorder ◽

Rapid Progression ◽

Sleep Behavior ◽

Risk Of Death ◽

Progression Of Disease

ObjectivesTo investigate (1) the prevalence of REM sleep behavior disorder (RBD) as mode of disease onset in a cohort of patients with multiple system atrophy (MSA) and (2) disease progression and prognosis in patients with MSA with RBD predating (pre-RBD) and following (post-RBD) disease onset.MethodsWe retrospectively identified all patients with a clinical diagnosis of MSA evaluated at least once a year during the disease course. Type of onset was defined by the first reported motor or autonomic symptom/sign related to MSA. The occurrence of symptoms/signs and milestone of disease progression, and their latency from disease onset, were collected. Survival data were calculated. RBD was confirmed by video-polysomnography.ResultsOf a total of 158 patients, pre-RBD represented the mode of disease onset in 27% of patients, preceding disease onset according to the international criteria with a median of 3 (2–5) years. Comparing pre-RBD and post-RBD patients, the first group showed an increased prevalence of autonomic onset of disease, a reduced prevalence of parkinsonism, an earlier onset of stridor, pyramidal signs, symptomatic orthostatic hypotension, urinary dysfunction, severe dysphagia, and wheelchair dependency. The risk of death was higher in patients with pre-RBD.ConclusionsIn our MSA cohort, RBD represented the most frequent mode of disease presentation. A more rapid progression of disease was observed in the pre-RBD group. These findings suggested a careful assessment of sleep disorders to early recognize RBD and a closer follow-up of autonomic dysfunction and stridor in patients with pre-RBD.

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Emotional Lability at Disease Onset Is an Independent Prognostic Factor of Faster Disease Progression in Amyotrophic Lateral Sclerosis

Aging and Disease ◽

10.14336/ad.2019.1120 ◽

2020 ◽

Vol 11 (5) ◽

pp. 1021

Author(s):

Krzysztof Barć ◽

Katarzyna Szacka ◽

Krzysztof Nieporęcki ◽

Mamede de Carvalho ◽

Marta Gromicho ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Prognostic Factor ◽

Disease Progression ◽

Disease Onset ◽

Independent Prognostic Factor ◽

Emotional Lability ◽

Lateral Sclerosis

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Predictors of Hip Disease in the Systemic Arthritis Subtype of Juvenile Idiopathic Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.101146 ◽

2011 ◽

Vol 38 (5) ◽

pp. 954-958 ◽

Cited By ~ 7

Author(s):

MICHELLE BATTHISH ◽

BRIAN M. FELDMAN ◽

PAUL S. BABYN ◽

PASCAL N. TYRRELL ◽

RAYFEL SCHNEIDER

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Median Time ◽

Joint Destruction ◽

Disease Onset ◽

Systemic Jia ◽

Kaplan Meier ◽

Hip Disease ◽

The Mean ◽

Censored Observations ◽

Aggressive Interventions

Objective.Hip involvement occurs in 20%–40% of all cases of juvenile idiopathic arthritis (JIA). Patients with systemic JIA (sJIA) are affected most frequently. The aim of our study was to investigate the predictors of clinical hip disease and radiographic hip damage in sJIA.Methods.The medical records (1997–2007) of all children (n = 98) with sJIA were reviewed. Potential clinical and laboratory predictors were examined at presentation and at 3 and 6 months. To account for censored observations, we used survival analysis.Results.During the study period, 59 children met our inclusion criteria. The mean age at diagnosis was 7.8 years. Thirty patients (51%) developed clinical hip disease, with 12 (20%) developing radiographic evidence of hip damage. The median time to develop clinical hip disease was 24 months. Using Kaplan-Meier estimates, 25% of patients develop radiographically evident hip damage within 43 months. At presentation, patients in whom clinical hip disease later developed had polyarthritis (hazard ratio 2.51, p = 0.01), elevated IgG (HR 1.12, p = 0.01) and IgM (HR 2.71, p = 0.02), and higher CHAQ scores (HR 1.65, p = 0.02). At 3 months after disease onset, patients in whom radiographic hip damage later developed had fever (HR 4.78, p = 0.02), polyarthritis (HR 4.63, p = 0.02), and higher CHAQ scores (HR 3.20, p = 0.005). At 6 months, polyarthritis was the strongest predictor of both clinical hip disease and radiographic hip damage.Conclusion.Half of patients with sJIA develop clinical hip disease a median time of 24 months from diagnosis. Early identification of predictors of hip disease and damage in patients with sJIA may suggest earlier, more aggressive interventions to prevent joint destruction.

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Lymphatic Muscle Cells Contribute to Dysfunction of the Synovial Lymphatic System in Inflammatory Arthritis in Mice

10.21203/rs.3.rs-49472/v1 ◽

2020 ◽

Author(s):

Qianqian Liang ◽

Li Zhang ◽

Hao Xu ◽

Jinlong Li ◽

Yan Chen ◽

...

Keyword(s):

Inflammatory Arthritis ◽

Molecular Mechanisms ◽

Near Infrared ◽

Panax Notoginseng ◽

Muscle Cells ◽

Lv Function ◽

No Production ◽

Branch Points ◽

Hind Limbs ◽

And Function

Abstract Background. We previous studies reveal impaired draining function of the synovial lymphatic vessel (LV) contributes to inflammatory arthritis, but the cellular and molecular mechanisms involved are not fully understood.Objective. To investigate the involvement of lymphatic muscle cells (LMCs) in mediating impaired LV function in inflammatory arthritis.Methods. TNF transgenic (TNF-Tg) arthritic mice were used. Structure and function of the LVs that drain the hind limbs were examined by whole-mount immunofluorescence staining, electron microscope, and near-infrared lymphatic imaging. Primary LMCs were treated with TNF, and the changes in proliferation, apoptosis, and functional gene expression were assessed. Roles of the herbal drug, Panax Notoginseng Saponins (PNS), in arthritis and LVs were studied.Results. TNF-Tg mice developed ankle arthritis with age, which was associated with abnormalities of LVs: 1) dilated capillary LVs with few branch points; 2) mature LVs with reduced LMC coverage and draining function; 3) degenerative and apoptotic appearance of LMCs. TNF caused LMC apoptosis, reduced expression of muscle functional genes, and promoted the production of nitric oxide (NO) by lymphatic endothelial cells (LECs). PNS attenuated arthritis, restored LMC coverage and draining function of mature LVs, inhibited TNF-mediated NO expression, and reduced LMC apoptosis.Conclusion. The impaired draining function of LVs in TNF-Tg mice involves LMC apoptosis. TNF promotes LMC death directly and indirectly via NO production by LECs. PNS attenuates arthritis, improves LVs, and prevents TNF-induced LMC apoptosis by inhibiting NO production of LECs. LMCs contribute to the dysfunction of synovial LVs in inflammatory arthritis.

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Predicting Alzheimer’s disease progression trajectory and clinical subtypes using machine learning

10.1101/792432 ◽

2019 ◽

Author(s):

Vipul K. Satone ◽

Rachneet Kaur ◽

Anant Dadu ◽

Hampton Leonard ◽

Hirotaka Iwaki ◽

...

Keyword(s):

Machine Learning ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Progression ◽

Disease Onset ◽

Machine Learning Techniques ◽

Progression Rate ◽

Early Stages ◽

Age Related ◽

Learning Techniques

AbstractBackgroundAlzheimer’s disease (AD) is a common, age-related, neurodegenerative disease that impairs a person’s ability to perform day-to-day activities. Diagnosing AD is challenging, especially in the early stages. Many patients still go undiagnosed, partly due to the complex heterogeneity in disease progression. This highlights a need for early prediction of the disease course to assist its treatment and tailor therapy options to the disease progression rate. Recent developments in machine learning techniques provide the potential to not only predict disease progression and trajectory of AD but also to classify the disease into different etiological subtypes.Methods and findingsThe work shown here clusters participants in distinct and multifaceted progression subgroups of AD and discusses an approach to predict the progression rate from baseline diagnosis. We observed that the myriad of clinically reported symptoms summarized in the proposed AD progression space corresponds directly with memory and cognitive measures, which are routinely used to monitor disease onset and progression. Our analysis demonstrated accurate prediction of disease progression after four years from the first 12 months of post-diagnosis clinical data (Area Under the Curve of 0.96 (95% confidence interval (CI), 0.92-1.0), 0.81 (95% CI, 0.74-0.88) and 0.98 (95% CI, 0.96-1.0) for slow, moderate and fast progression rate patients respectively). Further, we explored the long short-term memory (LSTM) neural networks to predict the trajectory of an individual patient’s progression.ConclusionThe machine learning techniques presented in this study may assist providers in identifying different progression rates and trajectories in the early stages of the disease, hence allowing for more efficient and personalized healthcare deliveries. With additional information about the progression rate of AD at hand, providers may further individualize the treatment plans. The predictive tests discussed in this study not only allow for early AD diagnosis but also facilitate the characterization of distinct AD subtypes relating to trajectories of disease progression. These findings are a crucial step forward for early disease detection. These models can be used to design improved clinical trials for AD research.

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Recent advances in understanding frontotemporal degeneration

F1000Research ◽

10.12688/f1000research.20330.1 ◽

2019 ◽

Vol 8 ◽

pp. 2098

Author(s):

Barbara Borroni ◽

Alberto Benussi

Keyword(s):

Disease Progression ◽

Disease Onset ◽

Response To Treatment ◽

Future Research ◽

Frontotemporal Degeneration ◽

New Era ◽

Clinical Presentations ◽

Biological Aspects ◽

Core Issues ◽

Neuroimaging Techniques

Frontotemporal degeneration (FTD) is a heterogeneous spectrum of neurodegenerative disorders characterized by diverse clinical presentations, neuropathological characteristics, and underlying genetic causes. In the last few years, several advances in the knowledge of clinical and biological aspects have been accomplished and three major scenarios have emerged that will represent the core issues in the FTD scene over the next few years. Foremost, the development of cerebrospinal fluid and blood biomarkers as well as neuroimaging techniques will aid the pursuit of new diagnostic and prognostic markers able to identify the ongoing proteinopathy and predict disease progression, which is key in identifying and stratifying patients for enrolment in clinical trials as well as evaluating response to treatment. On the other hand, current research has focused on the first attempts to slow down or revert disease progression, with the identification of disease modulators associated with disease onset and the ongoing development of the first pharmacological treatments for both sporadic and genetic FTD. Future research will certainly improve our knowledge of FTD and possibly open up a new era of disease-modifying therapies for this still-orphan disorder.

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Lymphatic muscle cells contribute to dysfunction of the synovial lymphatic system in inflammatory arthritis in mice

10.21203/rs.3.rs-49472/v2 ◽

2021 ◽

Author(s):

Qianqian Liang ◽

Li Zhang ◽

Hao Xu ◽

Jinlong Li ◽

Yan Chen ◽

...

Keyword(s):

Inflammatory Arthritis ◽

Molecular Mechanisms ◽

Near Infrared ◽

Panax Notoginseng ◽

Muscle Cells ◽

Lv Function ◽

No Production ◽

Branch Points ◽

Hind Limbs ◽

And Function

Abstract Background. Our previous studies reveal that impaired draining function of the synovial lymphatic vessel (LV) contributes to the pathogenesis of inflammatory arthritis, but the cellular and molecular mechanisms involved are not fully understood.Objective. To investigate the involvement of lymphatic muscle cells (LMCs) in mediating impaired LV function in inflammatory arthritis. Methods. TNF transgenic (TNF-Tg) arthritic mice were used. Structure and function of the LVs that drained the hind limbs were examined by whole-mount immunofluorescence staining, electron microscopy, and near-infrared lymphatic imaging. Primary LMCs were treated with TNF, and the changes in proliferation, apoptosis, and functional gene expression were assessed. The roles of the herbal drug, Panax Notoginseng Saponins (PNS), in arthritis and LVs were studied.Results. TNF-Tg mice developed ankle arthritis with age, which was associated with abnormalities of LVs: 1) dilated capillary LVs with few branch points; 2) mature LVs with reduced LMC coverage and draining function; 3) degenerative and apoptotic appearance of LMCs. TNF caused LMC apoptosis, reduced expression of muscle functional genes, and promoted the production of nitric oxide (NO) by lymphatic endothelial cells (LECs). PNS attenuated arthritis, restored LMC coverage and draining function of mature LVs, inhibited TNF-mediated NO expression, and reduced LMC apoptosis. Conclusion. The impaired draining function of LVs in TNF-Tg mice involves LMC apoptosis. TNF promotes LMC death directly and indirectly via NO production by LECs. PNS attenuates arthritis, improves LVs, and prevents TNF-induced LMC apoptosis by inhibiting NO production of LECs. LMCs contribute to the dysfunction of synovial LVs in inflammatory arthritis.

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