Transcription factor EGR1 directs tendon differentiation and promotes tendon repair
Marie-Justine Guerquin, … , Francis Berenbaum, Delphine Duprez
Marie-Justine Guerquin, … , Francis Berenbaum, Delphine Duprez
Published August 1, 2013; First published July 25, 2013
Citation Information: J Clin Invest. 2013;123(8):3564-3576. https://doi.org/10.1172/JCI67521.
View: Text | PDF
Categories: Research Article Muscle biology

Transcription factor EGR1 directs tendon differentiation and promotes tendon repair

Abstract

Tendon formation and repair rely on specific combinations of transcription factors, growth factors, and mechanical parameters that regulate the production and spatial organization of type I collagen. Here, we investigated the function of the zinc finger transcription factor EGR1 in tendon formation, healing, and repair using rodent animal models and mesenchymal stem cells (MSCs). Adult tendons of Egr1–/– mice displayed a deficiency in the expression of tendon genes, including Scx, Col1a1, and Col1a2, and were mechanically weaker compared with their WT littermates. EGR1 was recruited to the Col1a1 and Col2a1 promoters in postnatal mouse tendons in vivo. Egr1 was required for the normal gene response following tendon injury in a mouse model of Achilles tendon healing. Forced Egr1 expression programmed MSCs toward the tendon lineage and promoted the formation of in vitro–engineered tendons from MSCs. The application of EGR1-producing MSCs increased the formation of tendon-like tissues in a rat model of Achilles tendon injury. We provide evidence that the ability of EGR1 to promote tendon differentiation is partially mediated by TGF-β2. This study demonstrates EGR1 involvement in adult tendon formation, healing, and repair and identifies Egr1 as a putative target in tendon repair strategies.

Authors

Marie-Justine Guerquin, Benjamin Charvet, Geoffroy Nourissat, Emmanuelle Havis, Olivier Ronsin, Marie-Ange Bonnin, Mathilde Ruggiu, Isabel Olivera-Martinez, Nicolas Robert, Yinhui Lu, Karl E. Kadler, Tristan Baumberger, Levon Doursounian, Francis Berenbaum, Delphine Duprez

×

Figure 4

Upregulation of tendon gene expression following injury.

Options: View larger image (or click on image) Download as PowerPoint
Upregulation of tendon gene expression following injury. (A) Longitudina...
(A) Longitudinal sections parallel to the axis of Achilles tendons were made in adult mice to create a mouse model for tendon injury. (B) We observed increased LacZ expression (reflecting Egr1 expression) in Achilles tendons 1 week after tendon injury in Egr1+/– mice. m, muscle. (C) qRT-PCR analyses of tendon-associated gene expression in injured tendons versus noninjured tendons 1 week after injury. The following tendon markers were analyzed: the tendon-associated transcription factors, Scx and Mkx; the tendon-associated collagens, Col1a1, Col1a2, Col3a1, Col5a1, Col6a1, Col12a1, and Col14a1; and the tendon-associated molecules, Tnmd, Tnc, Dcn, Bgn, Fn1, Fbn1, and Eln. mRNA levels of noninjured tendons were normalized to 1. Error bars represent SEM. *P < 0.05; **P < 0.01; ***P < 0.001, paired Student’s t tests. (D–I) Adjacent transverse sections of noninjured (D and E) and injured (F–I) Achilles tendons were hybridized with Egr1 (D, F, and H) or Col1a1 (E, G, and I) probes (blue labeling). Three weeks after injury, Egr1 and Col1a1 expression was upregulated in injured tendons at the site of injury compared with control (noninjured) tendons. Scale bars: 1 mm (A and B); 200 μm (D–G); 50 μm (H and I).