title: Matrix metalloprotease activity is an essential link between mechanical stimulus and mesenchymal stem cell behavior.
abstract: Progenitor cells are involved in the regeneration of the musculoskeletal system, which is known to be influenced by mechanical boundary conditions. Furthermore, matrix metalloproteases (MMPs) and tissue-specific inhibitors of metalloproteases (TIMPs) are crucial for matrix remodelling processes that occur during regeneration of bone and other tissues. This study has therefore investigated whether MMP activity affects mesenchymal stem cell (MSC) behavior and how MMP activity is influenced by the mechanical stimulation of these cells. Broad spectrum inhibition of MMPs altered the migration, proliferation, and osteogenic differentiation of MSCs. Expression analysis detected MMP-2, -3, -10, -11, -13, and -14, as well as TIMP-2, in MSCs at the mRNA and protein levels. Mechanical stimulation of MSCs led to an upregulation of their extracellular gelatinolytic activity, which was consistent with the increased protein levels seen for MMP-2, -3, -13, and TIMP-2. However, mRNA expression levels of MMPs/TIMPs showed no changes in response to mechanical stimulation, indicating an involvement of post-transcriptional regulatory processes such as alterations in MMP secretion or activation. One potential regulatory molecule might be the furin protease. Specific inhibition of MMP-2, -3, and -13 showed MMP-13 to be involved in osteogenic differentiation. The results of this study suggest that MSC function is controlled by MMP activity, which in turn is regulated by mechanical stimulation of cells. Thus, MMP/TIMP balance seems to play an essential role in transferring mechanical signals into MSC function. Disclosure of potential conflicts of interest is found at the end of this article.
authors.affiliation: Musculoskeletal Research Center Berlin, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, Germany. Grit.Kasper@charite.de
authors.forename: Grit
authors.initials: G
authors.lastname: Kasper
authors.forename: Juliane D
authors.initials: JD
authors.lastname: Glaeser
authors.forename: Sven
authors.initials: S
authors.lastname: Geissler
authors.forename: Andrea
authors.initials: A
authors.lastname: Ode
authors.forename: Jens
authors.initials: J
authors.lastname: Tuischer
authors.forename: Georg
authors.initials: G
authors.lastname: Matziolis
authors.forename: Carsten
authors.initials: C
authors.lastname: Perka
authors.forename: Georg N
authors.initials: GN
authors.lastname: Duda
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D045683:Furin / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D040542:Mechanotransduction, Cellular / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D008875:Middle Aged; D008954:Models, Biological; D009142:Musculoskeletal Physiological Phenomena / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics
chemical_list: D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D045683:Furin; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2