ABSTRACT
BACKGROUND: Linear morphoea (LM) is a rare connective tissue disorder characterized by a line of thickened skin and subcutaneous tissue and can also affect the underlying muscle and bone. Little is known about the disease aetiology, with treatment currently limited to immune suppression, and disease recurrence post-treatment is common. OBJECTIVES: In order to uncover new therapeutic avenues, the cell-intrinsic changes in LM fibroblasts compared with site-matched controls were characterized. METHODS: We grew fibroblasts from site-matched affected and unaffected regions from five patients with LM, we subjected them to gene expression analysis and investigation of SMAD signalling. RESULTS: Fibroblasts from LM lesions showed increased migration, proliferation, altered collagen processing, and abnormally high basal levels of phosphorylated SMAD2, thereby rendering them less responsive to transforming growth factor (TGF)-ß1 and reducing the degree of myofibroblast differentiation, which is a key component of the wound-healing and scarring process in normal skin. Conditioned media from normal fibroblasts could reverse LM-affected fibroblast migration and proliferation, suggesting that the LM phenotype is driven by an altered secretome. Gene array analysis and RNA-Seq indicated upregulation of ADAMTS8 and downregulation of FRAS1 and SOSTDC1. SOSTDC1 knock-down recapitulated the reduced TGF-ß1 responsiveness and LM fibroblast migration, while overexpression of ADAMTS8 induced myofibroblast markers. CONCLUSIONS: We demonstrate that cell-intrinsic changes in the LM fibroblast secretome lead to changes observed in the disease, and that secretome modulation could be a viable therapeutic approach in the treatment of LM.
Subject(s)
ADAMTS Proteins/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Fibroblasts/metabolism , Scleroderma, Localized/pathology , Skin/pathology , Adaptor Proteins, Signal Transducing/genetics , Adolescent , Animals , Biopsy , Cell Movement/genetics , Cell Proliferation/genetics , Child , Extracellular Matrix Proteins/metabolism , Female , Gene Knockdown Techniques , Humans , Male , Mice , NIH 3T3 Cells , Primary Cell Culture , RNA-Seq , Signal Transduction/genetics , Skin/cytology , Transforming Growth Factor beta1/metabolism , Up-RegulationABSTRACT
Although statins may increase glycaemia in type 2 diabetes, available data are from single-dose intervention trials or studies with no adjustment for concomitant changes in blood glucose-lowering therapy. To provide real-life data covering common statin types and doses, glycated haemoglobin (HbA1c) data from patients in the Fremantle Diabetes Study phases I (FDS1) and II (FDS2) and data on stable diabetes treatment before and after statin initiation were analysed. Intensity of statin therapy was categorized as low, moderate or high based on within-group dose regimens with similar serum LDL cholesterol-lowering effects. In pooled analyses of 335 eligible patients in FDS1 and FDS2, there was no change in HbA1c in the low-intensity group (0.04% or 0.4 mmol/mol; n = 159; p = .40), but a mean 0.22% (2.4 mmol/mol) increase in the moderate-intensity group (n = 185; p = .022) and a larger mean increase of 1.05% (11.5 mmol/mol) increase in the high-intensity group (n = 11; p = .023). These real-life data suggest a dose-response relationship between statin treatment intensity and glycaemia that has potential clinical implications.
