Conversion of Mechanical Force into TGF-β-Mediated Biochemical Signals

Abstract

Mechanical forces influence homeostasis in virtually every tissue [1–2]. Tendon, constantly exposed to variable mechanical force, is an excellent model in which to study the conversion of mechanical stimuli into a biochemical response [3–5]. Here we show in a mouse model of acute tendon injury and in vitro that physical forces regulate the release of active transforming growth factor (TGF)-β from the extracellular matrix (ECM). The quantity of active TGF-β detected in tissue exposed to various levels of tensile loading correlates directly with the extent of physical forces. At physiological levels, mechanical forces maintain, through TGF-β/Smad2/3-mediated signaling, the expression of Scleraxis (Scx), a transcription factor specific for tenocytes and their progenitors. The gradual and temporary loss of tensile loading causes reversible loss of Scx expression, whereas sudden interruption, such as in transection tendon injury, destabilizes the structural organization of the ECM and leads to excessive release of active TGF-β and massive tenocyte death, which can be prevented by the TGF-β type I receptor inhibitor SD208. Our findings demonstrate a critical role for mechanical force in adult tendon homeostasis. Furthermore, this mechanism could translate physical force into biochemical signals in much broader variety of tissues or systems in the body.

The development of zebrafish tendon and ligament progenitors

“…Muscle contraction is important in the development of many tissues, including the joints, cartilage and tendon-bone insertions (Kahn et al, 2009;Shwartz et al, 2012). Scx expression, in particular, is sensitive to changes in mechanical stimuli in adult tendons (Maeda et al, 2011). Furthermore, muscleless and aneural chick wings lose Scx expression in all regions of the proximal limb, and although no direct analysis of ligament fates was performed, Scx expression was absent in areas near cartilage elements (Edom-Vovard et al, 2002;Kardon, 1998).…”

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

“…An attractive model is one in which Scx (in concert with TGFβ signaling) shifts the fate of MSCs towards TPCs and initiates tendon ECM production, whereas factors expressed later in development, such as Mkx and Egr1, supplement the role of Scx by inducing the expression of ECM proteins as well as by repressing myogenic and skeletogenic fates. Furthermore, signaling mediated by mechanical forces upregulates expression of Scx, Mkx and Smad3, stimulating more ECM production, thereby providing positive feedback for fine-tuning tendon strength, as we discuss further below (Eliasson et al, 2008;Maeda et al, 2011).…”

“…5) (Liu et al, 2015). TGFβs are secreted bound to latent TGFβ-binding proteins (LTBPs), which form part of the large latency complex (LLC) in the ECM (Wipff et al, 2007;Maeda et al, 2011). They are also secreted along with latency-associated peptides (LAPs), which block association with TGFβ receptors, and along with other proteins of the LLC, they become incorporated into ECM via interactions between LTBPs and Fn, fibrillin or Dcn (Isogai et al, 2003;Rifkin, 2005;Farhat et al, 2012).…”

The characteristics of Ishikawa endometrial cancer cells are modified by substrate topography with cell-like features and the polymer surface

“…In other words, the structure of the neighborhood, as distinct from its composition, can affect cell functioning. 12,13 It is already known that tumors are often stiffer than healthy tissues, 14 thereby providing a different mechanical environment. Therefore, consideration of this aspect 15 is crucial in defining tumor development.…”