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.
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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

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Figure 8

EGR1 promotes the formation of tendon-like tissues in a rat model for tendon injury.

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EGR1 promotes the formation of tendon-like tissues in a rat model for te...
(A) Achilles tendons of adult nude rats were separated from the plantaris and soleus tendons. A total transverse section of the Achilles tendon was created, and both ends were immediately sutured back together with surgical sutures. C3H10T1/2 or C3H10T1/2-EGR1 cells were then implanted in the injured/sutured tendon. C3H10T1/2- and C3H10T1/2-EGR1–grafted tendons were morphologically and histologically analyzed by H&E staining of sections along the axis of the tendon, 2 (B–E) and 3 (F–I) weeks after manipulation. (F and G) Holes left by the suture points are indicated by ellipses. All the longitudinal sections (B–I) are orientated bone to the left and muscle to the right. (J) qRT-PCR analyses of tendon gene expression in nonmanipulated tendons, sham tendons (with no cell application), C3H10T1/2-grafted tendons, and C3H10T1/2-EGR1–grafted tendons 2 weeks after the operation. mRNA levels of nonmanipulated tendons were normalized to 1. (K) Collagen quantity was assessed using a hydroxyproline assay in nonmanipulated tendons, sham tendons, C3H10T1/2-grafted tendons, and C3H10T1/2-EGR1–grafted tendons 2 and 3 weeks postoperation. Error bars represent SD (J and K). *P < 0.05; **P < 0.01; ***P < 0.001, unpaired Student’s t tests. Scale bars: 1 cm (A); 1 mm (B, C, F, and G); 100 μm (D, E, H, and I).