title: Mechanical stimulation of human tendon stem/progenitor cells results in upregulation of matrix proteins, integrins and MMPs, and activation of p38 and ERK1/2 kinases.
abstract: BACKGROUND
  Tendons are dense connective tissues subjected periodically to mechanical stress upon which complex responsive mechanisms are activated. These mechanisms affect not only the development of these tissues but also their healing. Despite of the acknowledged importance of the mechanical stress for tendon function and repair, the mechanotransduction mechanisms in tendon cells are still unclear and the elucidation of these mechanisms is a key goal in tendon research. Tendon stem/progenitor cells (TSPC) possess common adult stem cell characteristics, and are suggested to actively participate in tendon development, tissue homeostasis as well as repair. This makes them an important cell population for tendon repair, and also an interesting research target for various open questions in tendon cell biology. Therefore, in our study we focused on TSPC, subjected them to five different mechanical protocols, and investigated the gene expression changes by using semi-quantitative, quantitative PCR and western blotting technologies.
  
  
  RESULTS
  Among the 25 different genes analyzed, we can convincingly report that the tendon-related genes - fibromodulin, lumican and versican, the collagen I-binding integrins - α1, α2 and α11, the matrix metalloproteinases - MMP9, 13 and 14 were strongly upregulated in TSPC after 3 days of mechanical stimulation with 8% amplitude. Molecular signaling analyses of five key integrin downstream kinases suggested that mechanical stimuli are mediated through ERK1/2 and p38, which were significantly activated in 8% biaxial-loaded TSPC.
  
  
  CONCLUSIONS
  Our results demonstrate the positive effect of 8% mechanical loading on the gene expression of matrix proteins, integrins and matrix metalloproteinases, and activation of integrin downstream kinases p38 and ERK1/2 in TSPC. Taken together, our study contributes to better understanding of mechanotransduction mechanisms in TPSC, which in long term, after further translational research between tendon cell biology and orthopedics, can be beneficial to the management of tendon repair.
authors.affiliation: Department of Surgery, Experimental Surgery and Regenerative Medicine, Ludwig-Maximilians-University (LMU), Nussbaumstr. 20, D-80336, Munich, Germany. tzvetan.popov@med.uni-muenchen.de.
authors.forename: Cvetan
authors.initials: C
authors.lastname: Popov
authors.affiliation: Department of Surgery, Experimental Surgery and Regenerative Medicine, Ludwig-Maximilians-University (LMU), Nussbaumstr. 20, D-80336, Munich, Germany. martina.burggraf@med.uni-muenchen.de.
authors.forename: Martina
authors.initials: M
authors.lastname: Burggraf
authors.affiliation: Institute of Orthopaedic Research and Biomechanics, University of Ulm, Helmholtzstr. 14, D-89081, Ulm, Germany. ludwika.kreja@uni-ulm.de.
authors.forename: Ludwika
authors.initials: L
authors.lastname: Kreja
authors.affiliation: Institute of Orthopaedic Research and Biomechanics, University of Ulm, Helmholtzstr. 14, D-89081, Ulm, Germany. anita.ignatius@uni-ulm.de.
authors.forename: Anita
authors.initials: A
authors.lastname: Ignatius
authors.affiliation: Department of Surgery, Experimental Surgery and Regenerative Medicine, Ludwig-Maximilians-University (LMU), Nussbaumstr. 20, D-80336, Munich, Germany. matthias.schieker@med.uni-muenchen.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schieker
authors.affiliation: Department of Surgery, Experimental Surgery and Regenerative Medicine, Ludwig-Maximilians-University (LMU), Nussbaumstr. 20, D-80336, Munich, Germany. denitsa.docheva@med.uni-muenchen.de.
authors.forename: Denitsa
authors.initials: D
authors.lastname: Docheva
mesh_terms: D000125:Achilles Tendon / Q000166:cytology* / Q000378:metabolism; D000328:Adult; D002454:Cell Differentiation; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D013314:Stress, Mechanical; D055815:Young Adult
chemical_list: D016023:Integrins; D020782:Matrix Metalloproteinases