Abstract
Mechanical loading of tendon cells results in an upregulation of mechanotransduction signaling pathways, cell-matrix adhesion and collagen synthesis, but whether unloading removes these responses is unclear. We investigated the response to tension release, with regard to matrix proteins, pro-inflammatory mediators and tendon phenotypic specific molecules, in an in vitro model where tendon-like tissue was engineered from human tendon cells. Tissue sampling was performed 1, 2, 4 and 6 days after surgical de-tensioning of the tendon construct. When tensile stimulus was removed, integrin type collagen receptors showed a contrasting response with a clear drop in integrin subunit α11 mRNA and protein expression, and an increase in α2 integrin mRNA and protein levels. Further, specific markers for tendon cell differentiation declined and normal tendon architecture was disturbed, whereas pro-inflammatory molecules were upregulated. Stimulation with the cytokine TGF-β1 had distinct effects on some tendon-related genes in both tensioned and de-tensioned tissue. These findings indicate an important role of mechanical loading for cellular and matrix responses in tendon, including that loss of tension leads to a decrease in phenotypical markers for tendon, while expression of pro-inflammatory mediators is induced.
Highlights
Tendon is a collagen-rich tissue that plays an indispensable role in locomotion and postural control, and its parallel arrangement of collagen fibrils along the tensional axis allows tendons to withstand high forces [1]
When tendon cells were cultured on 2D monolayer (‘‘2D cells’’) and compared to cells cultured in the fixed-length 3D tendonconstructs, there was a dramatic downregulation in gene expression of the tendon-specific TNMD and the transcription factors Mohawk homeobox (MKX), as well as a trend towards a lower SCX mRNA expression (p = 0.06) in 2D cell culture
For the other targets shown in figure 2, i.e. fibronectin (FN), TGF-b1 (TGFB1) and CCN2, there were no differences between cells grown on 2D monolayer and 3D tendon-constructs, CCN2 revealed a tendency towards a higher expression on 2D monolayer (p = 0.07)
Summary
Tendon is a collagen-rich tissue that plays an indispensable role in locomotion and postural control, and its parallel arrangement of collagen fibrils along the tensional axis allows tendons to withstand high forces [1]. Tendon injuries are a frequent problem and in general, the regeneration process of tendon pathologies is poor and often leads to fibrotic changes and inferior function of the tissue [6,7,8,9,10]. It has remained largely unknown what role the mechanical environment plays in the activation of catabolic changes of human tendon cells, which might explain the development of pathological changes and complication during the regeneration process. While not studied on MKX, both SCX and TNMD are linked to the mechanical and spatial extracellular environment [17,18], suggesting an association with the mechanical environment and markers of the tendon phenotype
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