Row Sindhu, Liu Yayu, Alimperti Stella, Agarwal Sandeep K, Andreadis Stelios T
Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Amherst, NY 14260, USA.
Section of Allergy, Immunology, and Rheumatology Biology, Inflammation Center, Baylor College of Medicine, Houston, TX 77030, USA.
J Cell Sci. 2016 Aug 1;129(15):2950-61. doi: 10.1242/jcs.183772. Epub 2016 Jun 16.
We discovered that Cadherin-11 (CDH11) regulates collagen and elastin synthesis, both affecting the mechanical properties and contractile function of animal tissues. Using a Cdh11-null mouse model, we observed a significant reduction in the mechanical properties [Youngs' modulus and ultimate tensile strength (UTS)] of Cdh11(-/-) as compared to wild-type (WT) mouse tissues, such as the aorta, bladder and skin. The deterioration of mechanical properties (Youngs' modulus and UTS) was accompanied by reduced collagen and elastin content in Cdh11(-/-) mouse tissues as well as in cells in culture. Similarly, knocking down CDH11 abolished collagen and elastin synthesis in human cells, and consequently reduced their ability to generate force. Conversely, engagement of CDH11 through homophilic interactions, led to swift activation of the TGF-β and ROCK pathways as evidenced by phosphorylation of downstream effectors. Subsequently, activation of the key transcription factors, MRTF-A (also known as MKL1) and MYOCD led to significant upregulation of collagen and elastin genes. Taken together, our results demonstrate a novel role of adherens junctions in regulating extracellular matrix (ECM) synthesis with implications for many important biological processes, including maintenance of tissue integrity, wound healing and tissue regeneration.
我们发现，钙黏蛋白-11（CDH11）可调节胶原蛋白和弹性蛋白的合成，二者均会影响动物组织的力学性能和收缩功能。利用Cdh11基因敲除小鼠模型，我们观察到，与野生型（WT）小鼠组织（如主动脉、膀胱和皮肤）相比，Cdh11基因敲除小鼠（Cdh11-/-）组织的力学性能[杨氏模量和极限抗拉强度（UTS）]显著降低。力学性能（杨氏模量和UTS）的恶化伴随着Cdh11基因敲除小鼠组织以及培养细胞中胶原蛋白和弹性蛋白含量的减少。同样，敲低人细胞中的CDH11可消除胶原蛋白和弹性蛋白的合成，从而降低其产生力的能力。相反，通过同源相互作用激活CDH11会导致TGF-β和ROCK信号通路迅速激活，下游效应分子的磷酸化证明了这一点。随后，关键转录因子MRTF-A（也称为MKL1）和MYOCD的激活导致胶原蛋白和弹性蛋白基因显著上调。综上所述，我们的研究结果表明黏附连接在调节细胞外基质（ECM）合成中具有新作用，这对许多重要的生物学过程具有重要意义，包括维持组织完整性、伤口愈合和组织再生。
