Abstract
Scleraxis is a basic helix-loop-helix transcription factor that plays a central role in promoting tenocyte proliferation and matrix synthesis during embryonic tendon development. However, the role of scleraxis in the growth and adaptation of adult tendons is not known. We hypothesized that scleraxis is required for tendon growth in response to mechanical loading and that scleraxis promotes the specification of progenitor cells into tenocytes. We conditionally deleted scleraxis in adult mice using a tamoxifen-inducible Cre-recombinase expressed from the Rosa26 locus (ScxΔ) and then induced tendon growth in Scx+ and ScxΔ adult mice via plantaris tendon mechanical overload. Compared with the WT Scx+ group, ScxΔ mice demonstrated blunted tendon growth. Transcriptional and proteomic analyses revealed significant reductions in cell proliferation, protein synthesis, and extracellular matrix genes and proteins. Our results indicate that scleraxis is required for mechanically stimulated adult tendon growth by causing the commitment of CD146+ pericytes into the tenogenic lineage and by promoting the initial expansion of newly committed tenocytes and the production of extracellular matrix proteins.
Highlights
Tendons are made up of an extracellular matrix (ECM) containing primarily type I collagen, as well as other collagens, elastin, and various proteoglycans [1]
To study the role of scleraxis in adult tendon growth, we generated Rosa26CreERT2/CreERT2 Scxfl/fl mice to allow for the inactivation of scleraxis upon treatment with tamoxifen, while Rosa26CreERT2/CreERT2 Scx+/+ mice maintain the expression of Scx after tamoxifen treatment
We induced a supraphysiological overload of the plantaris tendons of Scx+ and ScxΔ mice by synergist ablation and analyzed tendons at either 7 days (7D) or 14D after surgery (Figure 1, B and C)
Summary
Tendons are made up of an extracellular matrix (ECM) containing primarily type I collagen, as well as other collagens, elastin, and various proteoglycans [1]. Tendon ECM is arranged in a hierarchical manner, with densely packed collagen fibers wrapped by layers of basement membrane [1]. Tendon fibroblasts, are the main cell type in tendons and are thought to be responsible for the production, organization, and maintenance of the tendon ECM [2]. Tendons are surrounded by an outermost basement membrane called the epitenon, which provides blood and nerve supply to the tendon [1, 3]. The organization of the ECM allows the tendon to properly transmit forces from muscle to bone and allow for locomotion and to respond to mechanical stimuli [4, 5]. Mechanical loading can increase tendon cross-sectional area (CSA) up to 30% [6] and improve tendon mechanical properties [5, 7], but less is known about the cellular and molecular mechanisms behind tendon growth and adaptation in adult animals
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