Interference with the contractile machinery of the fibroblastic chondrocyte cytoskeleton induces re-expression of the cartilage phenotype through involvement of PI3K, PKC and MAPKs

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Author(s) Rottmar, Markus, Mhanna, Rami, Guimond-Lischer, Stefanie, Vogel, Viola, Zenobi-Wong, Marcy, Manuira-Weber, Katharina
Publication Type Journal Items, Publication Status: Published
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Title Interference with the contractile machinery of the fibroblastic chondrocyte cytoskeleton induces re-expression of the cartilage phenotype through involvement of PI3K, PKC and MAPKs
Author(s) Rottmar, Markus
Mhanna, Rami
Guimond-Lischer, Stefanie
Vogel, Viola
Zenobi-Wong, Marcy
Manuira-Weber, Katharina
Journal or Series Title Experimental cell research
Volume Number 320
Issue Number 2
Start Page 175
End Page 187
ISSN 0014-4827
1090-2422
Publisher Elsevier
Publication Place Amsterdam
Publication Date 2014-01
Keyword(s) Actin cytoskeleton
Cell contractility
Chondrocyte
ILK
MAPK
PI3K
PKC
Re-differentiation
Staurosporine
Extracellular signaling regulated kinase
Glycosaminoglycan
Integrin-linked kinase
Mitogen-activated protein kinase
Mitogen-activated protein kinase kinase
Phosphoinositide-3-kinase
Protein kinase C
Abstract Chondrocytes rapidly lose their phenotypic expression of collagen II and aggrecan when grown on 2D substrates. It has generally been observed that a fibroblastic morphology with strong actin-myosin contractility inhibits chondrogenesis, whereas chondrogenesis may be promoted by depolymerization of the stress fibers and/or disruption of the physical link between the actin stress fibers and the ECM, as is the case in 3D hydrogels. Here we studied the relationship between the actin-myosin cytoskeleton and expression of chondrogenic markers by culturing fibroblastic chondrocytes in the presence of cytochalasin D and staurosporine. Both drugs induced collagen II re-expression; however, renewed glycosaminoglycan synthesis could only be observed upon treatment with staurosporine. The chondrogenic effect of staurosporine was augmented when blebbistatin, an inhibitor of myosin/actin contractility, was added to the staurosporine-stimulated cultures. Furthermore, in 3D alginate cultures, the amount of staurosporine required to induce chondrogenesis was much lower compared to 2D cultures (0.625nM vs. 2.5nM). Using a selection of specific signaling pathway inhibitors, it was found that PI3K-, PKC- and p38-MAPK pathways positively regulated chondrogenesis while the ERK-pathway was found to be a negative regulator in staurosporine-induced re-differentiation, whereas down-regulation of ILK by siRNA indicated that ILK is not determining for chondrocyte re-differentiation. Furthermore, staurosporine analog midostaurin displayed only a limited chondrogenic effect, suggesting that activation/deactivation of a specific set of key signaling molecules can control the expression of the chondrogenic phenotype. This study demonstrates the critical importance of mechanobiological factors in chondrogenesis suggesting that the architecture of the actin cytoskeleton and its contractility control key signaling molecules that determine whether the chondrocyte phenotype will be directed along a fibroblastic or chondrogenic path.
DOI 10.1016/j.yexcr.2013.11.004
Document Type Article
Publication Status Published
Language English
Assigned Organisational Unit(s) 03640
03949
Organisational Unit(s)
NEBIS System Number 000977828
Source Database ID SCOPUS-84890858742
WOS-000330095100001
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@article{Rttmr2014,
  author = "Rottmar, Markus and Mhanna, Rami and Guimond-Lischer, Stefanie and Vogel, Viola and Zenobi-Wong, Marcy and Manuira-Weber, Katharina",
  title = "{I}nterference with the contractile machinery of the fibroblastic chondrocyte cytoskeleton induces re-expression of the cartilage phenotype through involvement of {P}{I}3{K}, {P}{K}{C} and {M}{A}{P}{K}s",
  journal = "Experimental cell research",
  year = 2014,
  volume = "320",
  number = "2",
  pages = "175--187",
  month = jan,
}


E-Citations record created: Tue, 07 Jan 2014, 06:58:57 CET