Division of Growth and Development, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
UCLA Division of Plastic and Reconstructive Surgery and Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Signal Transduct Target Ther. 2017;2:17050-. doi: 10.1038/sigtrans.2017.50. Epub 2017 Oct 13.
Blocking transforming growth factor (TGF)β1 signal transduction has been a central strategy for scar reduction; however, this approach appears to be minimally effective. Here, we show that fibromodulin (FMOD), a 59-kD small leucine-rich proteoglycan critical for normal collagen fibrillogenesis, significantly reduces scar formation while simultaneously increasing scar strength in both adult rodent models and porcine wounds, which simulate human cutaneous scar repair. Mechanistically, FMOD uncouples pro-migration/contraction cellular signals from pro-fibrotic signaling by selectively enhancing SMAD3-mediated signal transduction, while reducing AP-1-mediated TGFβ1 auto-induction and fibrotic extracellular matrix accumulation. Consequently, FMOD accelerates TGFβ1-responsive adult fibroblast migration, myofibroblast conversion, and function. Furthermore, our findings strongly indicate that, by delicately orchestrating TGFβ1 activities rather than indiscriminately blocking TGFβ1, FMOD elicits fetal-like cellular and molecular phenotypes in adult dermal fibroblasts and adult cutaneous wounds , which is a unique response of living system undescribed previously. Taken together, this study illuminates the signal modulating activities of FMOD beyond its structural support functions, and highlights the potential for FMOD-based therapies to be used in cutaneous wound repair.
阻断转化生长因子 (TGF)β1 信号转导一直是减少疤痕的核心策略；然而，这种方法似乎效果甚微。在这里，我们表明，纤维调蛋白 (FMOD)，一种 59kD 的小富含亮氨酸的蛋白聚糖，对正常胶原原纤维形成至关重要，可显著减少疤痕形成，同时增加成年啮齿动物模型和模拟人类皮肤疤痕修复的猪伤口的疤痕强度。从机制上讲，FMOD 通过选择性增强 SMAD3 介导的信号转导，同时减少 AP-1 介导的 TGFβ1 自动诱导和纤维细胞外基质积累，将促迁移/收缩细胞信号与促纤维化信号解偶联。因此，FMOD 加速了 TGFβ1 反应性成纤维细胞的迁移、肌成纤维细胞的转化和功能。此外，我们的研究结果强烈表明，FMOD 通过巧妙地协调 TGFβ1 的活性，而不是不加区分地阻断 TGFβ1，在成年真皮成纤维细胞和成年皮肤伤口中引发类似于胎儿的细胞和分子表型，这是以前未描述的生命系统的独特反应。总之，这项研究阐明了 FMOD 在其结构支持功能之外的信号调节活性，并强调了基于 FMOD 的疗法在皮肤伤口修复中的应用潜力。
