Osteoprotegerin (OPG) serum levels are associated with liver fibrogenesis and have been proposed as a biomarker for diagnosis. However, the source and role of OPG in liver fibrosis are unknown, as is the question of whether OPG expression responds to treatment. Therefore, we aimed to elucidate the fibrotic regulation of OPG production and its possible function in human and mouse livers. OPG levels were significantly higher in lysates of human and mouse fibrotic livers compared to healthy livers. Hepatic OPG expression localized in cirrhotic collagenous bands in and around myofibroblasts. Single cell sequencing of murine liver cells showed hepatic stellate cells (HSC) to be the main producers of OPG in healthy livers. Using mouse precision-cut liver slices, we found OPG production induced by transforming growth factor β1 (TGFβ1) stimulation. Moreover, OPG itself stimulated expression of genes associated with fibrogenesis in liver slices through TGFβ1, suggesting profibrotic activity of OPG. Resolution of fibrosis in mice was associated with decreased production of OPG compared to ongoing fibrosis. OPG may stimulate fibrogenesis through TGFβ1 and is associated with the degree of fibrogenesis. It should therefore be investigated further as a possible drug target for liver fibrosis or biomarker for treatment success of novel antifibrotics.

中文翻译：

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骨保护素在肝纤维化中不仅是可能的血清标志物：还涉及其在人和鼠肝中的功能研究。

骨保护素（OPG）血清水平与肝纤维化相关，并已被提议作为诊断的生物标志物。但是，OPG在肝纤维化中的来源和作用尚不清楚，OPG表达是否对治疗有反应也是一个问题。因此，我们旨在阐明OPG产生的纤维化调控及其在人和小鼠肝脏中的可能功能。与健康肝脏相比，人和小鼠纤维化肝脏裂解物中的OPG水平明显更高。肝OPG表达位于成肌纤维细胞内和周围的肝硬化胶原蛋白带中。鼠肝细胞的单细胞测序表明，肝星状细胞（HSC）是健康肝脏中OPG的主要产生者。使用小鼠精确切割的肝脏切片，我们发现了由转化生长因子β1（TGFβ1）刺激诱导的OPG产生。此外，OPG本身通过TGFβ1刺激了肝切片中与纤维化相关的基因的表达，提示OPG的纤维化活性。与正在进行的纤维化相比，小鼠纤维化的消退与OPG的产生减少有关。OPG可通过TGFβ1刺激纤维发生，并与纤维发生的程度有关。因此，应将其作为肝纤维化的可能药物靶标或新型抗纤维药物治疗成功的生物标志物进行进一步研究。