The transforming growth factor (TGF)-β/Smad signal transduction pathway is closely associated with hypertrophic scar (HS) formation. Smad interacting protein 1 (SIP1) is a cytoplasmic protein that efficiently regulates Smad2-/3-dependent signaling within the TGF-β₁ pathway. SIP1 influences collagen synthesis in the HS through a heretofore unknown mechanism. This study investigated the role of the SIP1-mediated TGF-β₁/Smad signaling pathway in extracellular matrix (ECM) protein production and hypertrophic scarring. SIP1 expression was markedly lower in HS vs. normal skin (NS) tissue, and α-smooth muscle actin (α-SMA) content and collagen I/III (Col I/III) synthesis were inversely correlated with SIP1 expression. Furthermore, SIP1 inhibited Smad2/3 phosphorylation in vitro, and improved the collagen-based architecture of the scar while reducing collagen expression and overall scar formation in a rabbit ear model of HS. Based on these findings, we propose that SIP1 acts as a molecular modulator capable of altering Smad2-/3-facilitated signaling through the control of Smad phosphorylation, thus inhibiting α-SMA and collagen upregulation in fibroblasts and, ultimately, HS formation. The low SIP1 content in scar tissue also suggests that SIP1 (and positive regulation thereof) is a prospective target for selective HS drug therapy.

中文翻译：

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Smad相互作用蛋白1在细胞外基质蛋白产生和肥厚性瘢痕形成中影响转化生长因子-β1/ Smad信号传导。

转化生长因子（TGF）-β/ Smad信号转导途径与肥厚性瘢痕（HS）形成密切相关。Smad蛋白相互作用蛋白1（SIP1）是细胞质蛋白能够有效地调节TGF-β内Smad2- / 3依赖性信号₁通路。SIP1通过迄今未知的机制影响HS中的胶原合成。这项研究调查了SIP1介导的TGF-β的作用₁/ Smad信号通路在细胞外基质（ECM）蛋白质产生和肥大性瘢痕形成中。HS与正常皮肤（NS）组织相比，SIP1表达明显降低，α平滑肌肌动蛋白（α-SMA）含量和胶原I / III（Col I / III）合成与SIP1表达成反比。此外，SIP1在体外抑制Smad2 / 3磷酸化，并改善了瘢痕的胶原蛋白结构，同时减少了HS兔耳模型中的胶原蛋白表达和总体瘢痕形成。基于这些发现，我们建议SIP1充当分子调节剂，能够通过控制Smad磷酸化来改变Smad2- / 3-促进的信号传导，从而抑制成纤维细胞中α-SMA和胶原的上调，并最终抑制HS的形成。