“We believe that EGR1 is acting upstream of other signalling pathways, including the TGF-β pathway, to promote tendon differentiation during development and repair,” says Delphine Duprez, summarizing the implications of a new animal study. By increasing our limited understanding of tendon differentiation, the research might aid the development of future therapies.

...EGR1-expressing MSCs showed greater efficacy ... in augmenting the formation of tendon-like tissues...

The transcription factor EGR1 has previously been shown to induce tendon gene expression in chick embryos. Building on that finding, the investigators showed that tendons from Egr1−/− mice had significantly decreased levels of mRNAs encoding the transcription factor scleraxis (specific to tendons and ligaments) and type I collagen (the main tendon collagen). Although of normal appearance at the macroscopic level, these tendons were shown to be reduced in number, diameter and strength. Furthermore, the upregulation of tendon gene expression following Achilles tendon injury was limited in Egr1−/− mice, implicating EGR1 in tendon repair as well as tendon development.

The researchers next examined whether forced expression of EGR1 in mouse mesenchymal stem cells (MSCs) would stimulate tendon cell differentiation. Indeed, EGR1 induced tendon gene expression and morphology, and prevented differentiation into the osteogenic or adipogenic lineages, although chondrogenic differentiation was not affected. Moreover, in a rat injury model, EGR1-expressing MSCs showed greater efficacy than MSCs lacking EGR1 expression in augmenting the formation of tendon-like tissues, suggesting that EGR1-expressing MSCs might have therapeutic potential in tendon repair. The MSCs were not integrated into the tendons, however, so how do they exert their effects? Further analyses indicated that EGR1 can bind to the Tgfb2 promoter and that it increases the levels of Tgfb2 mRNA in MSCs, thus suggesting that TGF-β2 partially mediates the tendon-promoting effects of EGR1.

So, this study highlights the important role of EGR1 in tendons. “The next step will be to characterize the mechanisms controlling EGR1 activation in tendons,” enthuses Duprez. “Our working hypothesis is focused on mechanical stimulation, since this is important for tendon formation and it is already known that EGR1 expression can be regulated by mechanical stimuli in other systems.”