Editors' ChoiceMechanotransduction

May the Force Be with Your Tenocytes

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Science Signaling  14 Jun 2011:
Vol. 4, Issue 177, pp. ec163
DOI: 10.1126/scisignal.4177ec163

Tendons, fibrous connective tissues that transmit force from skeletal muscle to bone, consist of specialized fibroblasts known as tenocytes, as well as abundant extracellular matrix (ECM). Maeda et al. used transgenic mice that expressed green fluorescent protein (GFP) under the control of the promoter of the tenocyte transcription factor Scleraxis (ScxGFP mice) to investigate the role of mechanical force in adult tendon homeostasis. In a complete transection model of acute tendon injury, which led to immediate loss of tensile load, they observed an increase in terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end labeling (TUNEL)–positive cells and a decrease in GFP intensity within 0.5 hour and a 70% loss in tenocytes compared with sham-operated tendons at 3 days. Intramuscular injection of botulinum toxin A (to gradually and reversibly decrease force) decreased GFP intensity at 1 week (without cell death), decreased abundance of collagen type 1 fibrils and cartilage oligomeric matrix protein, and decreased tendon stiffness and peak force; all of these showed some recovery 2 weeks postinjection. The intensity of GFP expression in primary cultures of tenocytes isolated from ScxGFP mice decreased to <30% of initial values after 48 hours in culture and to <5% by 6 days. Using a microfluidic device, the authors determined that application of shear stress promoted retention of ScxGFP expression and could also reverse the decline (when applied starting on day 7). Transforming growth factor (TGF)–β is activated and released from complexes with the ECM by injury and, of 11 cytokines and growth factors tested, TGF-β1, -2, and -3 were the most potent at increasing GFP intensity in tenocyte cultures. Moreover, the TGF-β type I receptor inhibitor SD208 decreased GFP intensity and Scx mRNA abundance in cultured tenocytes exposed to shear stress. SD208 also decreased the abundance of phosphorylated Smad2 in the nucleus of tenocytes under shear stress, and a Smad3 inhibitor decreased tenocyte GFP intensity and Scx mRNA abundance in response to either shear stress or TGF-β. Mechanical force increased the abundance of TGF-β1 mRNA in cultures of tenocytes lacking p53 and p21 (to increase yield), with force strength correlating with release of active TGF-β into culture media. It was intriguing that, whereas 80 pM TGF-β1 promoted retention of ScxGFP expression in cultured tenocytes, 160 pM promoted tenocyte death. Tendon transection led to the release of activated TGF-β, and pretreatment with SD208 reduced the number of postinjury TUNEL-positive cells. The authors propose therefore that the sudden loss of mechanical force leads to release of TGF-β from the ECM and, thereby, massive tenocyte death and that immediate application of TGF-β inhibitors to injured tendons could improve prognosis.

T. Maeda, T. Sakabe, A. Sunaga, K. Sakai, A. L. Rivera, D. R. Keene, T. Sasaki, E. Stavnezer, J. Iannotti, R. Schweitzer, D. Ilic, H. Baskaran, T. Sakai, Conversion of mechanical force into TGF-β-mediated biochemical signals. Curr. Biol. 21, 933–941 (2011). [PubMed]

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