Abstract
BackgroundTendon is a mechanical tissue that transmits forces generated by muscle to bone in order to allow body motion. The molecular pathways that sense mechanical forces during tendon formation, homeostasis and repair are not known. EGR1 is a mechanosensitive transcription factor involved in tendon formation, homeostasis and repair. We hypothesized that EGR1 senses mechanical signals to promote tendon gene expression.Methodology/Principal findingsUsing in vitro and in vivo models, we show that the expression of Egr1 and tendon genes is downregulated in 3D-engineered tendons made of mesenchymal stem cells when tension is released as well as in tendon homeostasis and healing when mechanical signals are reduced. We further demonstrate that EGR1 overexpression prevents tendon gene downregulation in 3D-engineered tendons when tension is released. Lastly, ultrasound and microbubbles mediated EGR1 overexpression prevents the downregulation of tendon gene expression during tendon healing in reduced load conditions.Conclusion/SignificanceThese results show that Egr1 expression is sensitive to mechanical signals in tendon cells. Moreover, EGR1 overexpression prevents the downregulation of tendon gene expression in the absence of mechanical signals in 3D-engineered tendons and tendon healing. These results show that EGR1 induces a transcriptional response downstream of mechanical signals in tendon cells and open new avenues to use EGR1 to promote tendon healing in reduced load conditions.
Highlights
Tendon is a crucial component of the musculo-skeletal system, which transmits forces generated by skeletal muscle to bone to allow body motion
We conclude that Egr1 expression is sensitive to tension in engineered mouse tendons and Early Growth Response-1 (EGR1) forced expression prevents the downregulation of tendon gene expression in the absence of mechanical input
We show that reduced load conditions consistently lead to a decrease in expression of the transcription factor Egr1 and tendon genes in tendon homeostasis, tendon healing and in vitro engineered tendons
Summary
Tendon is a crucial component of the musculo-skeletal system, which transmits forces generated by skeletal muscle to bone to allow body motion. Mechanical signals are known to be involved in tendon development, homeostasis and repair [1,2,3,4]. The bHLH transcription factor Scleraxis (Scx) is expressed in embryonic, fetal and postnatal tendons [6,7,8]. Tendon is a mechanical tissue that transmits forces generated by muscle to bone in order to allow body motion. The molecular pathways that sense mechanical forces during tendon formation, homeostasis and repair are not known. EGR1 is a mechanosensitive transcription factor involved in tendon formation, homeostasis and repair. We hypothesized that EGR1 senses mechanical signals to promote tendon gene expression
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