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.

The past, present and future in scaffold-based tendon treatments

“…increases revascularisation of repairing tendon tissue, improving overall healing [169]; plateletderived growth factor (PDGF) has beneficial effects on the functional repair of tendon tissue in the canine model, increasing tendon glide, but not mechanical properties, over a 42 day period [170]; basic fibroblast growth factor (bFGF) stimulates both MSC proliferation and differentiation towards tenogenic lineage, leading to increased expression of tendon specific ECM proteins and increased collagen production from cells [171]; bone morphogenic protein 12 (BMP-12), also referred to as growth differentiation factor 7 (GDF-7) induces both in vitro and in vivo tenogenesis of MSCs in both human and equine cells [172][173][174]; BMP-13 (GDF-6) induces an increase in the expression of tendon specific proteins in rat MSCs along with increasing the characteristic wave like pattern found in tendon histological samples after 14 days implantation in a rat Achilles defect model [175]; BMP-14 (GDF-5) reduces adhesion formation between tendons and surrounding tissues, improving overall function and recovery [176]; early growth response protein 1 (EGR1) directs tendon differentiation in rat MSCs and improve tendon healing in a rat Achilles tendon injury model [177]; and transforming growth factor-β (TGF-β) is highly influential in the recruitment and maintenance of TC progenitor cells during injury [178]. While these growth factors have demonstrated efficacy, as assessed by increased cellular migration, matrix production and matrix mechanical properties over a short period of time (up to around 8 weeks), little difference has been documented in long term tissue integration, matrix composition and overall tissue strength over control groups [177,178]. To this end, the use of single growth factor injections [179] or cocktails of thereof [180] at different healing stages has been proposed [181].…”

Tendon development and musculoskeletal assembly: emerging roles for the extracellular matrix

“…Flies lacking Sr function fail to form TPCs and display disrupted muscle patterning and attachments, whereas Sr overexpression transforms ectodermal progenitors into TPCs (Becker et al, 1997). Embryonic TPCs in mice express orthologs of Sr -Egr1 and Egr2 (Lejard et al, 2011) -and Egr1 is sufficient to induce Scx expression and specify MSCs as tenocytes in vitro (Guerquin et al, 2013). However, like Scx, both Egr1 and Egr2 appear to be dispensable for tenocyte specification, as Egr1…”

Transcriptomic analysis of mouse limb tendon cells during development

“…SCX has been shown to be required and sufficient for Tnmd expression (Docheva et al, 2005;Shukunami et al, 2006;Murchison et al, 2007). Two other DNA-binding proteins, namely the zinc-finger protein early growth response 1 (EGR1) and the homeodomain protein mohawk (MKX), have been shown to be involved in tendon formation (Ito et al, 2010;Liu et al, 2010;Lejard et al, 2011;Guerquin et al, 2013). However, these two transcription factors, although important for Col1a1 transcription in tendons, are not specific to tendons.…”