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Open Access 01-12-2018 | Research article

Blockade of TGF-β/Smad signaling by the small compound HPH-15 ameliorates experimental skin fibrosis

Authors: Vu Huy Luong, Takenao Chino, Noritaka Oyama, Takashi Matsushita, Yoko Sasaki, Dai Ogura, Shin-ichiro Niwa, Tanima Biswas, Akiyuki Hamasaki, Mikako Fujita, Yoshinari Okamoto, Masami Otsuka, Hironobu Ihn, Minoru Hasegawa

Published in: Arthritis Research & Therapy | Issue 1/2018

Abstract

Background

Transforming growth factor-β (TGF-β)/Smad signaling is well known to play a critical role in the pathogenesis of systemic sclerosis (SSc). We previously developed an artificial molecule, the histidine-pyridine-histidine ligand derivative HPH-15, which may have an antifibrotic effect. The purpose of the present study was to clarify the effects of this drug in human skin fibroblasts and in a preclinical model of SSc.

Methods

The effects of HPH-15 on expression of extracellular matrix components and TGF-β signaling in human dermal fibroblasts were analyzed. The antifibrotic properties of HPH-15 and its mechanisms were also examined in a bleomycin-induced skin fibrosis mouse model.

Results

HPH-15 suppressed the TGF-β-induced phosphorylation of Smad3 and inhibited the expression of collagen I, fibronectin 1, connective tissue growth factor, and α-smooth muscle actin induced by TGF-β in cultured human skin fibroblasts. In the bleomycin-induced skin fibrosis model, oral administration of HPH-15 protected against the development of skin fibrosis and ameliorated established skin fibrosis. Additionally, HPH-15 suppressed the phosphorylation of Smad3 in various cells, including macrophages in the bleomycin-injected skin. Further, in the treated mice, dermal infiltration of proinflammatory macrophages (CD11b⁺Ly6C^hi) and M2 profibrotic macrophages (CD11b⁺CD204⁺ or CD11b⁺CD206⁺) was significantly decreased during the early and late stages, respectively. HPH-15 treatment resulted in decreased messenger RNA (mRNA) expression of the M2 macrophage markers arginase 1 and Ym-1 in the skin, whereas it inversely augmented expression of Friend leukemia integration 1 and Krüppel-like factor 5 mRNAs, the transcription factors that repress collagen synthesis. No apparent adverse effects of HPH-15 were found during the treatment.

Conclusions

HPH-15 may inhibit skin fibrosis by inhibiting the phosphorylation of Smad3 in dermal fibroblasts and possibly in macrophages. Our results demonstrate several positive qualities of HPH-15, including oral bioavailability, a good safety profile, and therapeutic effectiveness. Thus, this TGF-β/Smad inhibitor is a potential candidate therapeutic for SSc clinical trials.

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Title: Blockade of TGF-β/Smad signaling by the small compound HPH-15 ameliorates experimental skin fibrosis
Authors: Vu Huy Luong
Takenao Chino
Noritaka Oyama
Takashi Matsushita
Yoko Sasaki
Dai Ogura
Shin-ichiro Niwa
Tanima Biswas
Akiyuki Hamasaki
Mikako Fujita
Yoshinari Okamoto
Masami Otsuka
Hironobu Ihn
Minoru Hasegawa
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Arthritis Research & Therapy / Issue 1/2018
Electronic ISSN: 1478-6362
DOI: https://doi.org/10.1186/s13075-018-1534-y

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Blockade of TGF-β/Smad signaling by the small compound HPH-15 ameliorates experimental skin fibrosis

Abstract

Background

Methods

Results

Conclusions

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Abstract

Background

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Conclusions

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