TGF-β Prevents Phosphate-Induced Osteogenesis through Inhibition of BMP and Wnt/β-Catenin Pathways

Abstract

BackgroundTransforming growth factor-β (TGF-β) is a key cytokine during differentiation of mesenchymal stem cells (MSC) into vascular smooth muscle cells (VSMC). High phosphate induces a phenotypic transformation of vascular smooth muscle cells (VSMC) into osteogenic-like cells. This study was aimed to evaluate signaling pathways involved during VSMC differentiation of MSC in presence or not of high phosphate.ResultsOur results showed that TGF-β induced nuclear translocation of Smad3 as well as the expression of vascular smooth muscle markers, such as smooth muscle alpha actin, SM22α, myocardin, and smooth muscle-myosin heavy chain. The addition of high phosphate to MSC promoted nuclear translocation of Smad1/5/8 and the activation of canonical Wnt/β-catenin in addition to an increase in BMP-2 expression, calcium deposition and alkaline phosphatase activity. The administration of TGF-β to MSC treated with high phosphate abolished all these effects by inhibiting canonical Wnt, BMP and TGF-β pathways. A similar outcome was observed in high phosphate-treated cells after the inhibition of canonical Wnt signaling with Dkk-1. Conversely, addition of both Wnt/β-catenin activators CHIR98014 and lithium chloride enhanced the effect of high phosphate on BMP-2, calcium deposition and alkaline phosphatase activity.ConclusionsFull VSMC differentiation induced by TGF-β may not be achieved when extracellular phosphate levels are high. Moreover, TGF-β prevents high phosphate-induced osteogenesis by decreasing the nuclear translocation of Smad 1/5/8 and avoiding the activation of Wnt/β-catenin pathway.

Design of a Novel 3D Printed Bioactive Nanocomposite Scaffold for Improved Osteochondral Regeneration

“…Both nHA and nHA + TGF-β1 containing nanocomposite scaffolds exhibited increased extracellular calcium deposition of 29% and 24% and 24% and 38% after 1 and 2 weeks culture, respectively, when compared to control. This may be attributed to inhibition of phosphate-induced osteogenesis by TGF-β1 as reported by Guerrero et al 38 …”

The role of the progressive ankylosis protein (ANK) in adipogenic/osteogenic fate decision of precursor cells

“…Previous studies from our and other laboratories have shown that extracellular Pi stimulates osteogenic differentiation [2, 40, 41]. Interestingly, a recent study has shown that high extracellular Pi induced phenotypic transformation of vascular smooth muscle cells into osteogenic-like cells via the activation of Wnt/β-catenin signaling in these cells [42]. Our previous study, however, also suggested that extracellular PPi directly stimulates osteogenesis [2, 43].…”

3, 3′, 5‐triiodo‐L‐thyronine Increases In Vitro Chondrogenesis of Mesenchymal Stem Cells From Human Umbilical Cord Stroma Through SRC2

“…C and D). Dickkopf‐related protein 1 (DKK‐1) is a member of the Dkk protein family and an antagonist for Wnt signalling [Guerrero et al, ; Liu et al, ], which inhibits the translocation of β‐catenin into the nucleus and its link on LRP5/6 component. Supplementation of Dkk‐1 into CM plus T3 did not diminished levels of β‐catenin in spheroid after 14 days because the expression of β‐catenin increased comparing with CM alone plus Dkk‐1 and this increasing was statistically significant ( P < 0.05) by western blot analysis (Fig.…”