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 July 25, 2013
Citation Information: J Clin Invest. 2013;123(8):3564-3576. https://doi.org/10.1172/JCI67521.
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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 1

Multiscale analysis of tendons from adult Egr1–/– mice.

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Multiscale analysis of tendons from adult Egr1–/– mice. (A and B) Macr...
(A and B) Macroscopic views showing tail tendons of mouse tails close to the body from 2-month-old WT (A) and Egr1–/– (B) mice. (C) Number of tail tendons counted at the same level (close to the body) from 2- to 3-month-old WT and Egr1–/– mutant mice. (D) Tail tendon diameters from 2- to 3-month-old WT and Egr1–/– mice. (E) Examples of isolated tail tendons from WT and Egr1–/– mice. (F) Hoechst staining of individual tail tendons from WT and Egr1–/– mice. (G) Number of nuclei per unit area in tail tendon sections from 2- to 3-month-old age-matched WT and Egr1–/– mice. Numbers of nuclei were normalized to those in WT mice. (H and I) Electron microscopic analysis of tail tendons from 2-month-old WT and Egr1–/– mice. (J) Histograms showing the frequencies of fibril diameters from WT versus Egr1–/– mice. For WT mice, the mean of the diameters = 143.89 nm; SD = 87.63. For Egr1–/–, the mean of the diameters = 183.73 nm; SD = 84.88. (K) Interfibrillar area (per unit area) of tail tendons from WT and Egr1–/– mice. The error bars represent the SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Scale bars: 1 mm (A and B); 100 μm (E and F); 200 nm (H and I).