Cadherin-11 is a novel regulator of extracellular matrix synthesis and tissue mechanics.
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.
Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Amherst, NY 14260, USA.
Sindhu
S
Row
Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Amherst, NY 14260, USA.
Yayu
Y
Liu
Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Amherst, NY 14260, USA.
Stella
S
Alimperti
Section of Allergy, Immunology, and Rheumatology Biology, Inflammation Center, Baylor College of Medicine, Houston, TX 77030, USA.
Sandeep K
SK
Agarwal
Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, Amherst, NY 14260, USA Department of Biomedical Engineering, University at Buffalo, State University of New York, Amherst, NY 14260, USA Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY 14203, USA sandread@buffalo.edu.
Stelios T
0000-0001-9885-0457
ST
Andreadis
D000818:Animals; D001696:Biomechanical Phenomena; D015820:Cadherins / Q000172:deficiency / Q000378:metabolism*; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D020405:Dermis / Q000166:cytology; D055119:Elastic Modulus; D004549:Elastin / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013718:Tensile Strength; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D000099251:Myocardin
D015820:Cadherins; D003094:Collagen; D004549:Elastin; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D054460:rho-Associated Kinases; D000099251:Myocardin; C431575:MRTFA protein, human; C086960:osteoblast cadherin
Cadherin-11; Collagen; Elastin; Extracellular matrix; MRTF-A; Mechanical properties; Myocardin; Tissue regeneration