Conversion of mechanical force into TGF-β-mediated biochemical signals

Curr Biol. 2011 Jun 7;21(11):933-41. doi: 10.1016/j.cub.2011.04.007. Epub 2011 May 19.

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 a much broader variety of tissues or systems in the body.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Achilles Tendon / injuries
  • Achilles Tendon / metabolism
  • Achilles Tendon / pathology
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / analysis
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Death
  • Extracellular Matrix / metabolism
  • Green Fluorescent Proteins / analysis
  • Mechanotransduction, Cellular / physiology*
  • Mice
  • Physical Stimulation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors
  • Tendon Injuries / metabolism*
  • Tendon Injuries / pathology
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / physiology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Receptors, Transforming Growth Factor beta
  • Scx protein, mouse
  • Transforming Growth Factor beta
  • Green Fluorescent Proteins
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I