Wednesday, June 13, 2012

Gaining Stature with TGF-BetaR II

We know the importance of TGF-Beta in inducing chondrogenic differentiation and compounds like Endoglin can determine whether TGF-Beta goes down 1/5/8 or 2/3 Smad Pathway.  LSJL proceeds through the TGF-Beta type I pathway.

Type II TGFβ receptor modulates chondrocyte phenotype

"This pathology during which chondrocytes undergo modifications of their phenotype may result from alteration of transforming growth factor β (TGFβ) signaling. This study investigates the role of TGFβ response in the process of chondrocyte dedifferentiation/redifferentiation. Dedifferentiation was induced by successive passages of human articular chondrocytes, whereas their redifferentiation was performed by three-dimensional culture in alginate. Human mesenchymal stem cells were obtained from bone marrow and differentiated into chondrocyte-like phenotype by three-dimensional culture, embedded in the same scaffold. Protein and mRNA levels were analyzed by Western blot and real-time reverse transcription PCR. Regulatory mechanism was investigated using specific inhibitors (mithramycin), mRNA silencing or decoy oligonucleotides, and expression vectors. Chondrocyte dedifferentiation interfered with TGFβ signaling by decreasing TβRII mRNA and protein levels and subsequent TGFβ response[So TGF-Beta RII decrease may be part of the reduction in height growth with age]. TβRII ectopic expression in passaged chondrocytes permitted to increase the expression of several matrix genes, such as aggrecan or type II collagen. Redifferentiation of passaged chondrocytes permitted to restore, at least in part, TβRII expression and was related to differentiation of human bone marrow mesenchymal stem cells toward chondrocytes, where both specific protein 1 (Sp1) and TβRII mRNA levels were increased. Moreover, Sp1 manipulation by silencing or ectopic expression and pharmacologic inhibition revealed a link between expression levels of this transcriptional factor, which is crucial for constitutive expression of TβRII in cartilage, and TGFβ response[So increasing levels of Sp1 may help with chondrogenic differentiation as well]. Therefore, these data permit us to suggest an important role of TβRII expression in the maintenance of chondrocyte phenotype, which is altered with age, and bring new insights in our understanding of chondrogenesis process."

"Upon ligand binding, TβRI is phosphorylated by TβRII, resulting in activation of intracellular proteins, named Smads. Receptor-regulated Smads (R-Smads: Smad2 and Smad3) are phosphorylated by TβRI. Phosphorylated R-Smads form heterodimers with common-partner Smad (Co-Smads: Smad4) and translocate into the nucleus where they bind to specific DNA sequences for activation of the TGFβ target gene transcription. Inhibitory Smads (I-Smads: Smad7) inhibit phosphorylation of R-Smads by competing with their binding to activated TβRI. Recently, it was shown that besides signaling via TβRI (activin-like kinase 5, ALK5), TGFβ can also signal via ALK1, thereby activating Smad1/5/8 instead of Smad2/3"

"Serial passages of chondrocytes in serum-supplemented medium did not modulate significantly Smad2 and Smad4 mRNA levels. Moreover, they increased Smad3 mRNA levels whereas they decreased the expression of the I-Smad, Smad7. These data suggest that the loss of TGFβ responsiveness observed in dedifferentiated chondrocytes is independent of Smads expression level, since an upregulation of Smad3 and downregulation of Smad7 are usually associated with the activation of TGFβ signaling."<-Thus cell responsive to TGF-Beta may be more dependent on TGFBetaRII expression than Smad expression levels.

"Chondrocyte dedifferentiation, which occurs with aging, is likely associated to alteration of cell responsiveness to TGFβ by reduction of the TβRII expression"<-Loss of TGFBetaRII expression may reduce response to potential chondroinductors like LSJL.

" we speculate that the increased Smad3 expression observed during dedifferentiation and aging could be a compensatory mechanism to promote the chondrocyte phenotype"<-So increasing Smad3 expression could be a way to help grow taller.

"TβRII downregulation induced by retinoid acid treatment inhibits chondrogenesis of mouse embryonic palate mesenchymal cells"<-RA upregulates F-Spondin which is height decreasing.  Perhaps these height decreasing effects involve TGFBetaRII expression level reduction.

How to increase levels of TGFBetaRII, Smad3, and Sp1?  Reducing RA levels may not be an option as RA is a part of Vitamin A which is an essential nutrient.

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