Crucial transcription factors in tendon development and differentiation: their potential for tendon regeneration

Abstract

Tendons that connect muscles to bone are often the targets of sports injuries. The currently unsatisfactory state of tendon repair is largely attributable to the limited understanding of basic tendon biology. A number of tendon lineage-related transcription factors have recently been uncovered and provide clues for the better understanding of tendon development. Scleraxis and Mohawk have been identified as critical transcription factors in tendon development and differentiation. Other transcription factors, such as Sox9 and Egr1/2, have also been recently reported to be involved in tendon development. However, the molecular mechanisms and application of these transcription factors remain largely unclear and this prohibits their use in tendon therapy. Here, we systematically review and analyze recent findings and our own data concerning tendon transcription factors and tendon regeneration. Based on these findings, we provide interaction and temporal programming maps of transcription factors, as a basis for future tendon therapy. Finally, we discuss future directions for tendon regeneration with differentiation and trans-differentiation approaches based on transcription factors.

Understanding Tendons: Lessons from Transgenic Mouse Models

“…In mice, FGF signaling starts from the upper myotome resulting in the activation of the mitogen-activated protein kinase pathway, E26 transformation-specific sequence (Ets) transcription factors, Phosphatidylinositol-4-phosphate 5-kinase (Pea3) and Ezrin/radixin/moesin (Erm). Lastly, Scx and transcription factor Mohawk (Mkx) promote final tendon lineage commitment and differentiation; this is characterized by the expression of collagen type I, type XIV, and tenomodulin (Tnmd) [1,9,10]; Tnmd is to date, the best-known mature marker for tendons [11–13]. …”

“…Early growth response 1 and 2 (Egr1/2) transcription factors act as molecular sensors for mechanical signals guiding the final steps of tendon maturation and production of collagen I, III, V, XIV, proteoglycans (decorin, fibromodulin, lumican), and tenomodulin. Figure was adapted from [10]. BMP, bone morphogenetic protein; FGF, fibroblast growth factors; SHH, sonic hedgehog.…”

“…On the other side, ventral midline sonic hedgehog expression can solely activate Pax1, which consequently has a negative effect on Scx, hindering its induction in the sclerotome [10]. While signals coming from the myotome positively influence axial tendon development, signals derived from the sclerotome have an adverse effect.…”

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

“…Only a handful of factors are known to help specify tenocyte progenitor cells (TPCs) at muscle attachments, induce them to differentiate, and maintain and repair them in the adult (Aslan et al, 2008;Huang et al, 2015;Liu et al, 2012Liu et al, , 2014Schweitzer et al, 2010;Yang et al, 2013). Studies in animal models (e.g.…”

Aligned Nanofiber Topography Directs the Tenogenic Differentiation of Mesenchymal Stem Cells

“…Scaffold directed MSC differentiation is determined through a combination of morphology, panels of tendon-related markers, collagen production and alignment, and levels of glycosaminoglycan (GAG) content [7,8]. Scleraxis (SCX), a transcription factor, is a key tendon-related marker which functions in tendon development and differentiation and promotes the expression and production of type I collagen (COL I) [9][10][11]. Type I collagen is the main reference to monolayer.…”