Osteoprotegerin (OPG), a decoy receptor for receptor activator of NF-kB ligand (RANKL), is used as a biomarker for assessing severity of liver fibrosis. However, its expression and role in pulmonary fibrosis are unknown. We hypothesized that OPG also has a role in pulmonary fibrosis. Human and mouse control and fibrotic lung tissue were used to examine OPG expression, and mouse precision-cut lung slices to study OPG regulation in pulmonary fibrosis. Serum from idiopathic pulmonary fibrosis (IPF) patients and controls was analysed to investigate whether OPG levels correlate with disease status as measured by lung function. OPG-protein levels were significantly higher in mouse and human fibrotic lung tissue compared to control. OPG-mRNA and protein production were induced in mouse precision-cut-lung slices upon TGFbeta stimulation and could be inhibited with galunisertib, a TGFbeta receptor kinase inhibitor. OPG-protein levels in fibrotic mouse lung tissue correlated with degree of fibrosis. Isolated lung fibroblasts from IPF patients had higher OPG-protein levels than control fibroblasts. Serum OPG levels in IPF patients, at first presentation, negatively correlated with diffusing capacity to carbon monoxide. Finally, serum OPG levels higher than 1234 pg/ml at first presentation were associated with progression of disease in IPF patients. In conclusion, OPG is produced in lung tissue, associates with fibrosis, and may be a potential prognostic biomarker for IPF disease progression. Validation in a larger cohort is warranted to further explore the role of OPG in pulmonary fibrosis and its potential for assessing the prognosis of fibrotic lung disease in individual patients.

中文翻译：

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骨保护素在肺纤维化中升高，并与IPF进展相关

骨保护素（OPG）是NF-kB配体的受体激活剂（RANKL）的诱饵受体，被用作评估肝纤维化严重程度的生物标志物。但是，其在肺纤维化中的表达和作用尚不清楚。我们假设OPG在肺纤维化中也有作用。使用人和小鼠对照以及纤维化的肺组织检查OPG的表达，使用小鼠精密切割的肺切片研究OPG在肺纤维化中的调控。分析了特发性肺纤维化（IPF）患者和对照的血清，以调查OPG水平是否与肺功能所测疾病状态相关。与对照组相比，小鼠和人纤维化肺组织中的OPG蛋白水平明显更高。TGFβ刺激后，在小鼠精密切肺切片中诱导了OPG-mRNA和蛋白质的产生，并可以用TGFβ受体激酶抑制剂加尼西替尼（galunisertib）抑制。纤维化小鼠肺组织中的OPG蛋白水平与纤维化程度相关。从IPF患者中分离出的肺成纤维细胞的OPG蛋白水平高于对照成纤维细胞。首次出现IPF患者的血清OPG水平与向一氧化碳的扩散能力呈负相关。最后，首次出现时血清OPG水平高于1234 pg / ml与IPF患者的疾病进展有关。总之，OPG在肺组织中产生，与纤维化相关，并且可能是IPF疾病进展的潜在预后生物标志物。