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  1. IL-17A induction of ADAMTS-5 in differentiated THP-1 cells is modulated by the ERK signaling pathway
    Thou EMH, Choo QC, Chew CH
    Eur. Cytokine Netw., 2020 Jun 01;31(2):59-67.
    PMID: 32933893 DOI: 10.1684/ecn.2020.0446
    Atherosclerosis is initiated when lipoproteins are trapped by proteoglycans in the arterial intima. Macrophages play a vital role in this disease, especially in the formation of foam cells and the regulation of pro-inflammatory responses. They also participate in plaque stabilization through the secretion of matrix metalloproteinases. Studies have reported the role of ADAMTS proteases in osteoarthritis and atherosclerotic lesions.In the present study, we have studied the effect of interleukin-17A (IL-17A) on the expression of ADAMTS-5 in the macrophage cell line THP-1. The results show that the mRNA and protein expression levels of ADAMTS-5 were significantly upregulated when differentiated THP-1 cells were treated with 100 ng/mL of IL-17A for 24 h with maximum ADAMTS-5 mRNA expression levels obtained at 8 h of stimulation. Subsequent inhibition studies showed that IL-17A upregulation of ADAMTS-5 was mediated through ERK and JNK pathways in THP-1 cells. Phosphorylation studies revealed that the expression of ADAMTS-5 transcripts was upregulated by IL-17A through the activation of p-c-Raf (S338), p-MEK1/2 (Ser217/221), p-p44/42 MAPK (Thr202/Tyr204), and p-Elk1 (Ser383). ERK1/2 siRNA transfection further confirmed that the ERK pathway is involved in the expression of ADAMTS-5 in IL-17A-stimulated THP-1 cells.
    Matched MeSH terms: ADAMTS Proteins
  2. Fulltext Revealing hidden genetic diagnoses in the ocular anterior segment disorders
    Ma A, Yousoof S, Grigg JR, Flaherty M, Minoche AE, Cowley MJ, et al.
    Genet Med, 2020 10;22(10):1623-1632.
    PMID: 32499604 DOI: 10.1038/s41436-020-0854-x
    PURPOSE: Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion.

    METHODS: We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases.

    RESULTS: We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6.

    CONCLUSIONS: We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.

    Matched MeSH terms: ADAMTS Proteins
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