囊性纤维化中 GPNMB、磷酸化 ERK1/2 和 MMP-9 的增加与芳香硫酸酯酶 B 的减少有关。
Increased GPNMB, phospho-ERK1/2, and MMP-9 in cystic fibrosis in association with reduced arylsulfatase B.
机构信息
Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA; Jesse Brown VAMC, Chicago, IL, 60612, USA.
Department of Pediatrics, Rush University Medical Center, Chicago, IL 60612, USA.
出版信息
Mol Genet Metab. 2018 Jun;124(2):168-175. doi: 10.1016/j.ymgme.2018.02.012. Epub 2018 Feb 20.
BACKGROUND
GPNMB was increased in a CF gene array and in Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase)-null mice, consistent with previous reports that ARSB is reduced in cystic fibrosis (CF). Implications of GPNMB increase in CF are unknown.
METHODS
GPNMB levels were determined in serum and circulating leukocytes from CF patients and healthy controls. GPNMB binding with β-1 integrin and measurements of phospho-ERK1/2 and MMP-9 in CFTR-uncorrected, CFTR-corrected, and normal human bronchial epithelial cells (BEC) were determined, following ARSB and GPNMB knockdown, and treatment with RGD peptide, and ERK phosphorylation inhibitor.
RESULTS
GPNMB was markedly increased in CF patients compared to controls (p < 0.0001, unpaired t-test, two-tailed). Silencing GPNMB, treatment with excess RGD peptide, and treatment with ERK phosphorylation inhibitor blocked ARSB silencing-induced increases in MMP-9 in the normal BEC.
CONCLUSIONS
Findings suggest that decline in ARSB activity caused by decline in CFTR function leads to increased GPNMB, which may contribute to organ dysfunction in CF by increased MMP-9 expression.
背景
GPNMB 在 CF 基因阵列和 Arylsulfatase B（ARSB；N-乙酰半乳糖胺-4-硫酸酯酶）缺失的小鼠中增加，这与先前报道的 ARSB 在囊性纤维化（CF）中减少一致。CF 中 GPNMB 增加的影响尚不清楚。
方法
测定 CF 患者和健康对照者血清和循环白细胞中的 GPNMB 水平。在用 ARSB 和 GPNMB 敲低以及用 RGD 肽和 ERK 磷酸化抑制剂处理后，测定 CFTR 未校正、CFTR 校正和正常人类支气管上皮细胞（BEC）中 GPNMB 与 β-1 整合素的结合以及磷酸化 ERK1/2 和 MMP-9 的测量。
结果
与对照组相比，CF 患者的 GPNMB 明显增加（p<0.0001，未配对 t 检验，双尾）。沉默 GPNMB、用过量 RGD 肽处理和用 ERK 磷酸化抑制剂处理可阻断 ARSB 沉默诱导的正常 BEC 中 MMP-9 的增加。
结论
研究结果表明，CFTR 功能下降导致 ARSB 活性下降，从而导致 GPNMB 增加，这可能通过增加 MMP-9 表达导致 CF 中的器官功能障碍。
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