Abstract
BackgroundTransforming 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.MethodsThe 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.ResultsHPH-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+Ly6Chi) 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.ConclusionsHPH-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.
Highlights
Transforming growth factor-β (TGF-β)/Smad signaling is well known to play a critical role in the pathogenesis of systemic sclerosis (SSc)
histidine-pyridinehistidine ligand (HPH)-15 inhibits TGF-β-induced fibrotic responses in cultured human dermal fibroblasts Fibroblasts are the main source of collagen and other extracellular matrix (ECM) components in fibrotic skin
We first examined the biological effects of HPH-15 on in vitro ECM synthesis using human dermal fibroblasts
Summary
Transforming growth factor-β (TGF-β)/Smad signaling is well known to play a critical role in the pathogenesis of systemic sclerosis (SSc). Molecular-based approaches targeting the TGF-β cascade have not been established for the treatment of patients with SSc. molecular-based approaches targeting the TGF-β cascade have not been established for the treatment of patients with SSc For this reason, we sought to identify novel therapeutic modalities for SSc. We previously reported a series of symmetrically substituted 2,6-pyridine derivatives, histidine-pyridinehistidine ligand (HPH), possessing varied biological activities dependent on the structure of the 2,6-substituents. We previously reported a series of symmetrically substituted 2,6-pyridine derivatives, histidine-pyridinehistidine ligand (HPH), possessing varied biological activities dependent on the structure of the 2,6-substituents These activities include antitumor activity [16, 17], inhibition of zinc finger proteins [18], and inhibition of nuclear factor-κB [19]. We found novel antifibrotic activity of HPH-15 in several cell lines (Ogura D and Niwa S 2017, unpublished data)
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