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A novel inhibitor of Smad-dependent transcriptional activation suppresses tissue fibrosis in mouse models of systemic sclerosis.
Arthritis Rheum. 2009 Nov; 60(11):3465-75.AR

Abstract

OBJECTIVE

Tissue fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc), and an increasing number of promising molecular targets for antifibrotic therapies have been described recently. Transforming growth factor beta (TGFbeta) is well known to be the principal factor that leads to tissue fibrosis. The present study was undertaken to investigate the ability of HSc025, a novel small compound that antagonizes TGFbeta/Smad signaling through the activation of nuclear translocation of Y-box binding protein 1, to prevent tissue fibrosis in vitro or in mouse models of SSc.

METHODS

Human dermal fibroblasts were exposed to HSc025 at various concentrations in the presence of TGFbeta, and levels of collagen or fibronectin expression were determined. HSc025 (15 mg/kg/day for 14 days) was administered orally to tight skin mice and to mice with bleomycin-induced pulmonary fibrosis. Improvement of tissue fibrosis was evaluated by histologic or biochemical examination in each model.

RESULTS

Pretreatment with HSc025 prevented Smad-dependent promoter activation, in a dose-dependent manner; however, HSc025 had no effect on TGFbeta-induced phosphorylation of Smad3. The inhibitory effects of HSc025 on TGFbeta-induced collagen or fibronectin expression were also confirmed in vitro. Orally administered HSc025 significantly reduced hypodermal thickness and hydroxyproline content in tight skin mice, and markedly decreased the histologic score and hydroxyproline content in the lungs of bleomycin-treated mice.

CONCLUSION

These results demonstrate that HSc025 is a novel inhibitor of TGFbeta/Smad signaling, resulting in the improvement of skin and pulmonary fibrosis. Orally available HSc025 might therefore be useful in the treatment of SSc.

Authors+Show Affiliations

Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. minoruha@derma.m.kanazawa-u.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19877032

Citation

Hasegawa, Minoru, et al. "A Novel Inhibitor of Smad-dependent Transcriptional Activation Suppresses Tissue Fibrosis in Mouse Models of Systemic Sclerosis." Arthritis and Rheumatism, vol. 60, no. 11, 2009, pp. 3465-75.
Hasegawa M, Matsushita Y, Horikawa M, et al. A novel inhibitor of Smad-dependent transcriptional activation suppresses tissue fibrosis in mouse models of systemic sclerosis. Arthritis Rheum. 2009;60(11):3465-75.
Hasegawa, M., Matsushita, Y., Horikawa, M., Higashi, K., Tomigahara, Y., Kaneko, H., Shirasaki, F., Fujimoto, M., Takehara, K., & Sato, S. (2009). A novel inhibitor of Smad-dependent transcriptional activation suppresses tissue fibrosis in mouse models of systemic sclerosis. Arthritis and Rheumatism, 60(11), 3465-75. https://doi.org/10.1002/art.24934
Hasegawa M, et al. A Novel Inhibitor of Smad-dependent Transcriptional Activation Suppresses Tissue Fibrosis in Mouse Models of Systemic Sclerosis. Arthritis Rheum. 2009;60(11):3465-75. PubMed PMID: 19877032.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel inhibitor of Smad-dependent transcriptional activation suppresses tissue fibrosis in mouse models of systemic sclerosis. AU - Hasegawa,Minoru, AU - Matsushita,Yukiyo, AU - Horikawa,Mayuka, AU - Higashi,Kiyoshi, AU - Tomigahara,Yoshitaka, AU - Kaneko,Hideo, AU - Shirasaki,Fumiaki, AU - Fujimoto,Manabu, AU - Takehara,Kazuhiko, AU - Sato,Shinichi, PY - 2009/10/31/entrez PY - 2009/10/31/pubmed PY - 2010/1/5/medline SP - 3465 EP - 75 JF - Arthritis and rheumatism JO - Arthritis Rheum VL - 60 IS - 11 N2 - OBJECTIVE: Tissue fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc), and an increasing number of promising molecular targets for antifibrotic therapies have been described recently. Transforming growth factor beta (TGFbeta) is well known to be the principal factor that leads to tissue fibrosis. The present study was undertaken to investigate the ability of HSc025, a novel small compound that antagonizes TGFbeta/Smad signaling through the activation of nuclear translocation of Y-box binding protein 1, to prevent tissue fibrosis in vitro or in mouse models of SSc. METHODS: Human dermal fibroblasts were exposed to HSc025 at various concentrations in the presence of TGFbeta, and levels of collagen or fibronectin expression were determined. HSc025 (15 mg/kg/day for 14 days) was administered orally to tight skin mice and to mice with bleomycin-induced pulmonary fibrosis. Improvement of tissue fibrosis was evaluated by histologic or biochemical examination in each model. RESULTS: Pretreatment with HSc025 prevented Smad-dependent promoter activation, in a dose-dependent manner; however, HSc025 had no effect on TGFbeta-induced phosphorylation of Smad3. The inhibitory effects of HSc025 on TGFbeta-induced collagen or fibronectin expression were also confirmed in vitro. Orally administered HSc025 significantly reduced hypodermal thickness and hydroxyproline content in tight skin mice, and markedly decreased the histologic score and hydroxyproline content in the lungs of bleomycin-treated mice. CONCLUSION: These results demonstrate that HSc025 is a novel inhibitor of TGFbeta/Smad signaling, resulting in the improvement of skin and pulmonary fibrosis. Orally available HSc025 might therefore be useful in the treatment of SSc. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/19877032/A_novel_inhibitor_of_Smad_dependent_transcriptional_activation_suppresses_tissue_fibrosis_in_mouse_models_of_systemic_sclerosis_ DB - PRIME DP - Unbound Medicine ER -