Science Translational Medicine | FGFR3激活了一系列纤维化通路促...
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Science Translational Medicine
Aberrant activation of fibroblasts with progressive deposition of extracellular matrix is a key feature of systemic sclerosis (SSc), a prototypical idiopathic fibrotic disease. Here, the investigators demonstrate that the profibrotic cytokine transforming growth factor β selectively up-regulates fibroblast growth factor receptor 3 (FGFR3) and its ligand FGF9 to promote fibroblast activation and tissue fibrosis, leading to a prominent FGFR3 signature in the SSc skin. Transcriptome profiling, in silico analysis and functional experiments revealed that FGFR3 induces multiple profibrotic pathways including endothelin, interleukin-4, and connective tissue growth factor signaling mediated by transcription factor CREB (cAMP response element–binding protein). Inhibition of FGFR3 signaling by fibroblast-specific knockout of FGFR3 or FGF9 or pharmacological inhibition of FGFR3 blocked fibroblast activation and attenuated experimental skin fibrosis in mice. These findings characterize FGFR3 as an upstream regulator of a network of profibrotic mediators in SSc and as a potential target for the treatment of fibrosis.
DOI: 10.1126/scitranslmed.aaz5506
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Exome-wide association analysis suggests LRP2BP as a susceptibility gene for endothelial injury in systemic sclerosis in Han Chinese population
Journal of Investigative Dermatology
Genetic factors play a key role in the pathogenesis of autoimmune diseases while remains largely unknown. Herein, the investigators performed an exome-wide association study of systemic sclerosis (SSc) in Han Chinese population. In the discovery stage, 527 SSc patients and 5024 controls were recruited and genotyped. In validation study, an independent sample set of 479 patients and 1096 controls were examined. In total, they found four independent signals reached genome-wide significances. Among them, rs7574865 (Pcombined = 3.87 ×10-12) located within STAT4 was identified previously using samples of European-ancestry. Additionally, another signal including three SNPs in linkage-disequilibrium (LD) might be unreported susceptibility loci located in the epidermis differentiation complex (EDC) region. Furthermore, two SNPs located within the exon 3 of IGHM (rs45471499, Pcombined = 1.15×10-9) and upstream of LRP2BP (rs4317244, Pcombined = 4.17×10-8) were found. Moreover, rs4317244 was identified as an eQTL for LRP2BP that regulates the tight junction, cell cycle, and apoptosis in endothelial cell lines. Collectively, the results found three previously unreported signals associated with SSc in Han Chinese, and suggested the importance of LRP2BP in SSc pathogenesis. Given the limited sample size and discrepancies between previous results and their study, further studies in multi-ethnic populations are required for verification.
Doi: 10.1016/j.jid.2020.07.039
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