Friday, August 28, 2009

Tall with Vimentin?

The intermediate filament vimentin regulates chondrogenesis of adult human bone marrow-derived multipotent progenitor cells.

"Actin and tubulin [regulate] developmental chondrogenesis. Vimentin [regulates[ the chondrogenic differentiation of adult multipotent progenitor cells (MPCs). As our model of adult progenitor cell chondrogenesis, we employed high-density pellet cultures of human bone marrow-derived MPCs. siRNA-mediated knockdown of vimentin mRNA and protein triggered a reduction in the extent of MPC cartilage formation, as evidenced by depressed accumulation of mRNAs for the cartilage-specific marker genes aggrecan and collagen type II, as well as reduced levels of Alcian blue-stainable proteoglycan and collagen II protein in the extracellular matrix. Moreover, mRNA and protein levels for the chondro-regulatory transcription factors SOX5, SOX6, and SOX9 were diminished by vimentin knockdown. Depleted cellular vimentin also induced a drastic reduction in PKA phosphorylation levels but did not affect the phosphorylation of multiple other chondro-regulatory kinases and transcription factors, including ERK1/2, p38, Smad2, and Smad1/5/8. Importantly, siRNA-mediated knockdown of PKA C-alpha mRNA and protein mimicked the reduction in chondrogenesis caused by diminished cellular vimentin. Finally, overexpression of vimentin in MPCs significantly enhanced the activity of a transfected collagen II promoter-luciferase reporter gene."

"actin transduces the chondro-inhibitory effects of integrin adhesion in bovine bone marrow-derived mesenchymal stem cells (MSCs) cultured in an agarose hydrogel three-dimensional environment"

"dedifferentiated chondrocytes can be stimulated to re-express genes encoding cartilage-specific ECM molecules via cytochalasin-induced actin disruption"

"depleted cellular vimentin is associated with significantly depressed PKA phosphorylation levels and correspondingly that siRNA-mediated knockdown of PKA C-α mRNA and protein mimics the chondro-inhibitory effects of vimentin depletion. Finally, we found that vimentin overexpression markedly enhances adult human MPC pellet culture chondrogenesis."

"PKA C-α knockdown decreased AGC, COL2A1, SOX9, L-SOX5, and SOX6 mRNA transcript levels relative to negative controls"

"A plethora of intracellular signaling pathways have been implicated in the regulation of cartilage formation in embryonic chondro-progenitor cells, chondrogenic cell lines, and adult MSCs, including the Smad1/5/8 and 2/3 pathways, as well as the PKA, ERK1/2, p38, and JNK cascades"<-LSJL involves Smad1/5/8, ERK1/2, and P38.

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