Cargando…

Circulating bone morphogenetic protein 8A is a novel biomarker to predict advanced liver fibrosis

BACKGROUND & AIMS: Advanced hepatic fibrosis is the main risk factor of liver-related morbidity and mortality in patients with chronic liver disease. In this study, we assessed the potential role of bone morphogenetic protein 8A (BMP8A) as a novel target involved in liver fibrosis progression. M...

Descripción completa

Detalles Bibliográficos
Autores principales: Marañón, Patricia, Isaza, Stephania C., Fernández-García, Carlos Ernesto, Rey, Esther, Gallego-Durán, Rocío, Montero-Vallejo, Rocío, de Cía, Javier Rodríguez, Ampuero, Javier, Valverde, Ángela M., Romero-Gómez, Manuel, García-Monzón, Carmelo, González-Rodríguez, Águeda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10142503/
https://www.ncbi.nlm.nih.gov/pubmed/37106416
http://dx.doi.org/10.1186/s40364-023-00489-2
_version_ 1785033628760145920
author Marañón, Patricia
Isaza, Stephania C.
Fernández-García, Carlos Ernesto
Rey, Esther
Gallego-Durán, Rocío
Montero-Vallejo, Rocío
de Cía, Javier Rodríguez
Ampuero, Javier
Valverde, Ángela M.
Romero-Gómez, Manuel
García-Monzón, Carmelo
González-Rodríguez, Águeda
author_facet Marañón, Patricia
Isaza, Stephania C.
Fernández-García, Carlos Ernesto
Rey, Esther
Gallego-Durán, Rocío
Montero-Vallejo, Rocío
de Cía, Javier Rodríguez
Ampuero, Javier
Valverde, Ángela M.
Romero-Gómez, Manuel
García-Monzón, Carmelo
González-Rodríguez, Águeda
author_sort Marañón, Patricia
collection PubMed
description BACKGROUND & AIMS: Advanced hepatic fibrosis is the main risk factor of liver-related morbidity and mortality in patients with chronic liver disease. In this study, we assessed the potential role of bone morphogenetic protein 8A (BMP8A) as a novel target involved in liver fibrosis progression. METHODS: Histological assessment and BMP8A expression were determined in different murine models of hepatic fibrosis. Furthermore, serum BMP8A was measured in mice with bile duct ligation (BDL), in 36 subjects with histologically normal liver (NL) and in 85 patients with biopsy-proven non-alcoholic steatohepatitis (NASH): 52 with non- or mild fibrosis (F0-F2) and 33 with advanced fibrosis (F3-F4). BMP8A expression and secretion was also determined in cultured human hepatocyte-derived (Huh7) and human hepatic stellate (LX2) cells stimulated with transforming growth factor ꞵ (TGFꞵ). RESULTS: Bmp8a mRNA levels were significantly upregulated in livers from fibrotic mice compared to control animals. Notably, serum BMP8A levels were also elevated in BDL mice. In addition, in vitro experiments showed increased expression and secretion to the culture supernatant of BMP8A in both Huh7 and LX2 cells treated with TGFꞵ. Noteworthy, we found that serum BMP8A levels were significantly higher in NASH patients with advanced fibrosis than in those with non- or mild fibrosis. In fact, the AUROC of circulating BMP8A concentrations to identify patients with advanced fibrosis (F3-F4) was 0.74 (p˂0.0001). Moreover, we developed an algorithm based on serum BMP8A levels that showed an AUROC of 0.818 (p˂0.0001) to predict advanced fibrosis in NASH patients. CONCLUSION: This study provides experimental and clinical evidence indicating that BMP8A is a novel molecular target linked to liver fibrosis and introduces an efficient algorithm based on serum BMP8A levels to screen patients at risk for advanced hepatic fibrosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40364-023-00489-2.
format Online
Article
Text
id pubmed-10142503
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-101425032023-04-29 Circulating bone morphogenetic protein 8A is a novel biomarker to predict advanced liver fibrosis Marañón, Patricia Isaza, Stephania C. Fernández-García, Carlos Ernesto Rey, Esther Gallego-Durán, Rocío Montero-Vallejo, Rocío de Cía, Javier Rodríguez Ampuero, Javier Valverde, Ángela M. Romero-Gómez, Manuel García-Monzón, Carmelo González-Rodríguez, Águeda Biomark Res Research BACKGROUND & AIMS: Advanced hepatic fibrosis is the main risk factor of liver-related morbidity and mortality in patients with chronic liver disease. In this study, we assessed the potential role of bone morphogenetic protein 8A (BMP8A) as a novel target involved in liver fibrosis progression. METHODS: Histological assessment and BMP8A expression were determined in different murine models of hepatic fibrosis. Furthermore, serum BMP8A was measured in mice with bile duct ligation (BDL), in 36 subjects with histologically normal liver (NL) and in 85 patients with biopsy-proven non-alcoholic steatohepatitis (NASH): 52 with non- or mild fibrosis (F0-F2) and 33 with advanced fibrosis (F3-F4). BMP8A expression and secretion was also determined in cultured human hepatocyte-derived (Huh7) and human hepatic stellate (LX2) cells stimulated with transforming growth factor ꞵ (TGFꞵ). RESULTS: Bmp8a mRNA levels were significantly upregulated in livers from fibrotic mice compared to control animals. Notably, serum BMP8A levels were also elevated in BDL mice. In addition, in vitro experiments showed increased expression and secretion to the culture supernatant of BMP8A in both Huh7 and LX2 cells treated with TGFꞵ. Noteworthy, we found that serum BMP8A levels were significantly higher in NASH patients with advanced fibrosis than in those with non- or mild fibrosis. In fact, the AUROC of circulating BMP8A concentrations to identify patients with advanced fibrosis (F3-F4) was 0.74 (p˂0.0001). Moreover, we developed an algorithm based on serum BMP8A levels that showed an AUROC of 0.818 (p˂0.0001) to predict advanced fibrosis in NASH patients. CONCLUSION: This study provides experimental and clinical evidence indicating that BMP8A is a novel molecular target linked to liver fibrosis and introduces an efficient algorithm based on serum BMP8A levels to screen patients at risk for advanced hepatic fibrosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40364-023-00489-2. BioMed Central 2023-04-27 /pmc/articles/PMC10142503/ /pubmed/37106416 http://dx.doi.org/10.1186/s40364-023-00489-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Marañón, Patricia
Isaza, Stephania C.
Fernández-García, Carlos Ernesto
Rey, Esther
Gallego-Durán, Rocío
Montero-Vallejo, Rocío
de Cía, Javier Rodríguez
Ampuero, Javier
Valverde, Ángela M.
Romero-Gómez, Manuel
García-Monzón, Carmelo
González-Rodríguez, Águeda
Circulating bone morphogenetic protein 8A is a novel biomarker to predict advanced liver fibrosis
title Circulating bone morphogenetic protein 8A is a novel biomarker to predict advanced liver fibrosis
title_full Circulating bone morphogenetic protein 8A is a novel biomarker to predict advanced liver fibrosis
title_fullStr Circulating bone morphogenetic protein 8A is a novel biomarker to predict advanced liver fibrosis
title_full_unstemmed Circulating bone morphogenetic protein 8A is a novel biomarker to predict advanced liver fibrosis
title_short Circulating bone morphogenetic protein 8A is a novel biomarker to predict advanced liver fibrosis
title_sort circulating bone morphogenetic protein 8a is a novel biomarker to predict advanced liver fibrosis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10142503/
https://www.ncbi.nlm.nih.gov/pubmed/37106416
http://dx.doi.org/10.1186/s40364-023-00489-2
work_keys_str_mv AT maranonpatricia circulatingbonemorphogeneticprotein8aisanovelbiomarkertopredictadvancedliverfibrosis
AT isazastephaniac circulatingbonemorphogeneticprotein8aisanovelbiomarkertopredictadvancedliverfibrosis
AT fernandezgarciacarlosernesto circulatingbonemorphogeneticprotein8aisanovelbiomarkertopredictadvancedliverfibrosis
AT reyesther circulatingbonemorphogeneticprotein8aisanovelbiomarkertopredictadvancedliverfibrosis
AT gallegoduranrocio circulatingbonemorphogeneticprotein8aisanovelbiomarkertopredictadvancedliverfibrosis
AT monterovallejorocio circulatingbonemorphogeneticprotein8aisanovelbiomarkertopredictadvancedliverfibrosis
AT deciajavierrodriguez circulatingbonemorphogeneticprotein8aisanovelbiomarkertopredictadvancedliverfibrosis
AT ampuerojavier circulatingbonemorphogeneticprotein8aisanovelbiomarkertopredictadvancedliverfibrosis
AT valverdeangelam circulatingbonemorphogeneticprotein8aisanovelbiomarkertopredictadvancedliverfibrosis
AT romerogomezmanuel circulatingbonemorphogeneticprotein8aisanovelbiomarkertopredictadvancedliverfibrosis
AT garciamonzoncarmelo circulatingbonemorphogeneticprotein8aisanovelbiomarkertopredictadvancedliverfibrosis
AT gonzalezrodriguezagueda circulatingbonemorphogeneticprotein8aisanovelbiomarkertopredictadvancedliverfibrosis