title: Mechanical strain enhances extracellular matrix-induced gene focusing and promotes osteogenic differentiation of human mesenchymal stem cells through an extracellular-related kinase-dependent pathway.
abstract: Human mesenchymal stem cells (hMSCs) are a population of multipotent bone marrow cells capable of differentiating along multiple lineages, including bone. Our recently published proteomics studies suggest that focusing of gene expression is the basis of hMSC osteogenic transdifferentiation, and that extracellular matrix proteins play an important role in controlling this focusing. Here, we show that application of a 3-5% tensile strain to a collagen I substrate stimulates osteogenesis in the attached hMSCs through gene focusing via a MAP kinase signaling pathway. Mechanical strain increases expression levels of well-established osteogenic marker genes while simultaneously reducing expression levels of marker genes from three alternate lineages (chondrogenic, adipogenic, and neurogenic). Mechanical strain also increases matrix mineralization (a hallmark of osteogenic differentiation) and activation of extracellular signal-related kinase 1/2 (ERK). Addition of the MEK inhibitor PD98059 to reduce ERK activation decreases osteogenic gene expression and matrix mineralization while also blocking strain-induced down-regulation of nonosteogenic lineage marker genes. These results demonstrate that mechanical strain enhances collagen I-induced gene focusing and osteogenic differentiation in hMSCs through the ERK MAP kinase signal transduction pathway.
authors.affiliation: Department of Biology, Rensselaer Polytechnic Institute, Troy, NY 12180-3596, USA.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Ward
authors.forename: Roman M
authors.initials: RM
authors.lastname: Salasznyk
authors.forename: Robert F
authors.initials: RF
authors.lastname: Klees
authors.forename: Julianne
authors.initials: J
authors.lastname: Backiel
authors.forename: Phaedra
authors.initials: P
authors.lastname: Agius
authors.forename: Kristin
authors.initials: K
authors.lastname: Bennett
authors.forename: Adele
authors.initials: A
authors.lastname: Boskey
authors.forename: George E
authors.initials: GE
authors.lastname: Plopper
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000166:cytology*; D020411:Oligonucleotide Array Sequence Analysis; D010012:Osteogenesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D017550:Spectroscopy, Fourier Transform Infrared; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D013314:Stress, Mechanical
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D005419:Flavonoids; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one