PTP4A1 promotes TGFβ signaling and fibrosis in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and internal organs. Protein tyrosine phosphatases have received little attention in the study of SSc or fibrosis. Here, we show that the tyrosine phosphatase PTP4A1 is highly expressed in fibroblasts from patients with SSc. PTP4A1 and its close homolog PTP4A2 are critical promoters of TGFβ signaling in primary dermal fibroblasts and of bleomycin-induced fibrosis in vivo. PTP4A1 promotes TGFβ signaling in human fibroblasts through enhancement of ERK activity, which stimulates SMAD3 expression and nuclear translocation. Upstream from ERK, we show that PTP4A1 directly interacts with SRC and inhibits SRC basal activation independently of its phosphatase activity. Unexpectedly, PTP4A2 minimally interacts with SRC and does not promote the SRC-ERK-SMAD3 pathway. Thus, in addition to defining PTP4A1 as a molecule of interest for TGFβ-dependent fibrosis, our study provides information regarding the functional specificity of different members of the PTP4A subclass of phosphatases

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INTRODUCTION: Elderly patients with haemophilia (PWH) suffer from both haemarthrosis and haemophilic arthropathy (HA). Diagnosis of haemarthrosis in PWH is currently based on clinical presentation. No diagnostic protocols or validated criteria are available to identify haemarthrosis or to differentiate haemarthrosis from HA. AIM: The aim of this study is to identify symptoms and signs that can be used to differentiate haemarthrosis from HA. METHODS: A narrative literature review was performed on symptoms associated with haemarthrosis and symptoms associated with HA. Additionally, literature on the diagnosis of haemarthrosis in patients without haemophilia, imaging techniques and biomarkers was searched. RESULTS: This review shows that there is no consensus about the symptoms associated with haemarthrosis and that there is limited literature about the symptoms associated with HA. Additionally, symptoms associated with haemarthrosis partly overlap with symptoms of HA, particularly those symptoms associated with flare-ups of HA. Due to the overlap in symptoms differentiating between these conditions is complex. Furthermore, differentiating based on imaging techniques or biomarkers causes practical difficulties. CONCLUSION: Despite the overlap in symptoms, differentiating between joint bleeds and flare-ups of HA based on clinical presentation still seems the most convenient and practical solution. Further research is necessary to identify specific symptoms that can be used to differentiate between the two conditions

Safety of procuring research tissue during a clinically indicated kidney biopsy from patients with lupus: data from the Accelerating Medicines Partnership RA/SLE Network

Objectives In lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis.Methods 475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines.Results 34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved.Conclusions Procurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required

Value of routine ultrasound in detecting early joint changes in children with haemophilia using the 'Haemophilia Early Arthropathy Detection with UltraSound' protocol

INTRODUCTION: Patients with haemophilia tend to bleed in large joints even during prophylactic replacement therapy. Detection of early blood-induced joint changes may improve monitoring of treatment. The aim of this study was to explore the value of routine ultrasound in detecting early joint abnormalities in children with haemophilia on prophylaxis. METHODS: Sixty-four joints in 32 children with haemophilia were examined by one operator using the Haemophilia Early Arthropathy Detection with UltraSound protocol during annual multidisciplinary follow-up. Based on reported bleeding, the joint with the highest risk of blood-induced joint damage and the contralateral joint were examined. At the same day, clinical function was assessed according to the Haemophilia Joint Health Score (HJHS). RESULTS: Median age was 11.5 years (range = 5.5-16.4). Out of the 64 examined joints, one ankle was excluded because of previous surgery. Median lifetime joint bleeds/joint was three (interquartile ranges = 1-5). Clinical function of most joints was perfect: only 7/49 joints with reported bleeds scored positive due to swelling, muscle atrophy and/or range of motion loss (HJHS range = 1-2 points). Ultrasound showed abnormalities in 5/49 joints with reported bleeding, and 4/5 showed positive HJHS scores. Ultrasound abnormalities were present in 1/56 joints (1.8%, CI: 0.1-9.6%) without loss of clinical function. CONCLUSION: Ultrasound abnormalities were found during routine evaluation of joints in children with haemophilia on prophylaxis. Most joints with ultrasound abnormalities showed low HJHS scores too. Ultrasound could be used to evaluate whether minimal losses of clinical function might be caused by anatomical changes