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A micellized bone morphogenetic protein-7 prodrug ameliorates liver fibrosis by suppressing transforming growth factor- β signaling

Authors
 Kyungjoo Cho  ;  Nam Hee Kim  ;  Sang Hyun Seo  ;  Sang Hyun Song  ;  Chul Hee Jeong  ;  Hyun Sil Kim  ;  Jo Eun Um  ;  Minhee Ku  ;  Jaemoon Yang  ;  Jun Yong Park  ;  Sang Hoon Ahn  ;  Jong In Yook  ;  Seung Up Kim 
Citation
 AMERICAN JOURNAL OF CANCER RESEARCH, Vol.12(2) : 763-778, 2022-02 
Journal Title
AMERICAN JOURNAL OF CANCER RESEARCH
ISSN
 2156-6976 
Issue Date
2022-02
Keywords
Bone morphogenetic protein ; liver fibrosis ; trans-activator of transcription-fusion polypeptide ; transforming growth factor
Abstract
Bone morphogenetic protein-7 (BMP-7) antagonizes transforming growth factor-β (TGF-β), which is critically involved in liver fibrogenesis. Here, we designed a micelle formulation consisting of a protein transduction domain (PTD) fused BMP-7 polypeptide (mPTD-BMP-7) to enhance endocytic delivery, and investigated its ability to ameliorate liver fibrosis. The mPTD-BMP-7 formulation was efficiently delivered into cells via endocytosis, where it inhibited TGF-β mediated epithelial-mesenchymal transition. After successfully demonstrating delivery of fluorescently labeled mPTD-BMP-7 into the murine liver in vivo, we tested the mPTD-BMP-7 formulation in a murine liver fibrosis model, developed by repeated intraperitoneal injection of hepatotoxic carbon tetrachloride, twice weekly from 4 to 16 weeks. mPTD-BMP-7 effects were tested by injecting the mPTD-BMP-7 formulation (or vehicle control) into the lateral tail at a dose of 50 (n=8) or 500 μg/kg (n=10), also twice per week from 4 to 16 weeks. Vehicle-treated control mice developed fibrous septa surrounding the liver parenchyma and marked portal-to-portal bridging with occasional nodules, whereas mice treated with mPTD-BMP-7 showed only fibrous expansion of some portal areas, with or without short fibrous septa. Using the Ishak scoring system, we found that the fibrotic burden was significantly lower in mPTD-BMP-7 treated mice than in control mice (all P<0.001). Treatment with mPTD-BMP-7 protected tight junctions between hepatocytes and reduced extracellular matrix protein levels. It also significantly decreased mRNA levels of collagen 1A, smooth muscle α-actin, and connective tissue growth factor compared with that in control mice (all P<0.001). Collectively, out results indicate that mPTD-BMP-7, a prodrug formulation of BMP-7, ameliorates liver fibrosis by suppressing the TGF-β signaling pathway in a murine liver fibrosis model.
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
Yonsei Authors
Ku, Min Hee(구민희) ORCID logo https://orcid.org/0000-0002-1674-1474
Kim, Seung Up(김승업) ORCID logo https://orcid.org/0000-0002-9658-8050
Kim, Hyun Sil(김현실) ORCID logo https://orcid.org/0000-0003-3614-1764
Park, Jun Yong(박준용) ORCID logo https://orcid.org/0000-0001-6324-2224
Ahn, Sang Hoon(안상훈) ORCID logo https://orcid.org/0000-0002-3629-4624
Yang, Jae Moon(양재문) ORCID logo https://orcid.org/0000-0001-7365-0395
Yook, Jong In(육종인) ORCID logo https://orcid.org/0000-0002-7318-6112
Jeong, Cheol-Hee(정철희) ORCID logo https://orcid.org/0000-0003-1260-076X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/188430
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