Fibroblast-specific targeting of bone morphogenetic protein signaling molecules does not alter the outcome of alcohol-associated chronic pancreatitis in mice

Authors

Kevin H. Shi, Department of Surgery, UTHealth, 6431 Fannin Street, Houston, TX 77030, United States.
Isabella E. Hernandez, Department of Surgery, UTHealth, 6431 Fannin Street, Houston, TX 77030, United States.
Amanda C. Bean, Department of Surgery, UTHealth, 6431 Fannin Street, Houston, TX 77030, United States.
Amy Qin, Department of Surgery, UTHealth, 6431 Fannin Street, Houston, TX 77030, United States.
Rachel R. Tindall, Department of Surgery, UTHealth, 6431 Fannin Street, Houston, TX 77030, United States.
Jiajing Li, Department of Surgery, UTHealth, 6431 Fannin Street, Houston, TX 77030, United States.
Yinjie Zhang, Department of Surgery, UTHealth, 6431 Fannin Street, Houston, TX 77030, United States.
Thomas H. Gomez, Center for Laboratory Animal Medicine and Care, UTHealth, 6431 Fannin Street, Houston, TX 77030, United States.
Mamoun Younes, Department of Pathology, George Washington University School of Medicine and Health Sciences, 2300 M Street, NW, Washington, DC 20037, United States.
Yanna Cao, Department of Surgery, UTHealth, 6431 Fannin Street, Houston, TX 77030, United States.
Tien C. Ko, Department of Surgery, UTHealth, 6431 Fannin Street, Houston, TX 77030, United States.

Document Type

Journal Article

Publication Date

11-16-2025

Journal

Alcohol and alcoholism (Oxford, Oxfordshire)

Volume

61

Issue

1

DOI

10.1093/alcalc/agaf072

Keywords

alcohol-associated chronic pancreatitis; bone morphogenetic protein signaling molecules; fibroblasts; knockout mice

Abstract

AIMS: Prolonged alcohol misuse is a common cause of chronic pancreatitis, a disease characterized by progressive pancreatic fibrosis. Currently, there are no specific therapies due to unclear mechanisms. To explore the molecular mechanisms in chronic pancreatitis, we focused on the bone morphogenetic protein (BMP) signaling pathway and reported an anti-fibrogenic role of BMP signaling and a pro-fibrogenic role of Gremlin1 (Grem1, an endogenous BMP antagonist) using constitutive global knockout (KO) mice of BMP receptor type II (Bmpr2) and Grem1. In this study, we generated fibroblast(f)-specific KO mouse lines, Bmpr2fKO, Bmpr2fKO; Activin receptor (Acvr)2a+/-, and Grem1fKO and evaluated the KO effects on alcohol-associated chronic pancreatitis (ACP). METHODS: Bmpr2fKO, Bmpr2fKO; Acvr2a+/-, and Grem1fKO were generated and ACP was induced in the mice fed with a 4% alcohol liquid diet and injected with cerulein for up to 4 weeks. The pancreata were collected, ACP severity was assessed by histopathological scores and fibrosis, and pancreatic BMP signaling molecule messenger ribonucleic acid (mRNA) levels were measured by quantitative PCR. RESULTS: ACP progressed in wild-type C57BL/6 mice in a time-dependent fashion, correlating with elevated mRNA levels of Col1a2, Bmp2, and Bmpr2. However, there were no significant differences in ACP severity observed in Bmpr2fKO, Bmpr2fKO; Acvr2a+/-, and Grem1fKO mice compared to the respective controls. CONCLUSIONS: Fibroblast-specific targeting of BMP signaling may not be sufficient to alter the outcome of ACP.

APA Citation

Shi, Kevin H.; Hernandez, Isabella E.; Bean, Amanda C.; Qin, Amy; Tindall, Rachel R.; Li, Jiajing; Zhang, Yinjie; Gomez, Thomas H.; Younes, Mamoun; Cao, Yanna; and Ko, Tien C., "Fibroblast-specific targeting of bone morphogenetic protein signaling molecules does not alter the outcome of alcohol-associated chronic pancreatitis in mice" (2025). GW Authored Works. Paper 8090.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8090

Department

Pathology