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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

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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 2

Molecular analyses of tendons from Egr1–/– mutant mice.

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Molecular analyses of tendons from Egr1–/– mutant mice.
 
(A–C) qRT-PCR ...
(A–C) qRT-PCR analyses of tendon gene expression in Egr1–/– versus WT mice. The following tendon markers were analyzed: the tendon-associated transcription factors, Scx and Mkx (A); the tendon-associated collagens, Col1a1, Col1a2, Col3a1, Col5a1, Col6a1, Col12a1, and Col14a1; (B) and the tendon-associated molecules, Tnmd, Tnc, Dcn, Bgn, Fn1, Fbn1, and Eln (C). mRNA levels of tendon markers in WT tendons were normalized to 1. Error bars represent SEM. *P < 0.05; **P < 0.01; ***P < 0.001, unpaired Student’s t tests. (D and E) ChIP assays were performed on tendons from postnatal mice with antibodies against EGR1 and EGR2 or ACH4 (acetylated histone H4) as a positive control, or with GFP antibody as a negative control. ChIP products were analyzed by PCR to study the interaction of EGR1 with the tendon regulatory regions of mouse Col1a1 and Col1a2 promoters. Primers targeting a 230-bp region flanking the tendon-specific elements TSE1 and TSE2 and targeting a 330-bp region within the tendon-specific deletion identified DNA regions immunoprecipitated by EGR1 (D). Primers targeting a 73-bp fragment of the Col1a2 promoter identified DNA regions immunoprecipitated by EGR1 (E).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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