This reaction most likely resulted from TG2 induced inhibition of PKA signaling. Similarly, improved differentiation of human osteoblasts was reported on TG2 treated collagen form I scaffolds, even though the molecular mechanism of this regulation remains unclear. Hedgehog proteins are well-known as vital regulators of osteoblast maturation. Recently, TG2 induced oligomerization of hedgehog proteins was implicated as a putative mechanism within the regulation of bone formation. Inhibitors that block TG activity strongly decreased the amounts of chondrocyte secreted hedgehog protein oligomers. Moreover, a truncated 56kDa form of TG2, acting as an ATPase inside a Ca2 rich atmosphere, promoted matrix mineralization in preosteoblasts.
Inhibition of endogenous TG activity in preosteoblast cultures with cystamine resulted in comprehensive abrogation of mineralization, attributable to decreased ECM accumulation and an arrested state of osteoblast differentiation, yet, recent evidence indicated that FXIIIA selleck as opposed to TG2 acted as the key regulator of ECM deposition. Finally, TG2 induced osteoblast like transformation of phenotypically plastic cells, for example vascular smooth muscle cells, recommended that TG2 could possibly be essential for vascular calcification. 5. 4. 6. Vascular smooth muscle cells TG2 was shown to regulate the phenotypic stability of vascular smooth muscle cells. When grown on TG2 treated collagen matrices, vascular smooth muscle cells stabilized their contractile phenotype, showing that TG2 induced ECM modifications help their differentiated state. Similarly, norepinephrine induced contractility of these cells depended on TG2 mediated transamidation of cytoplasmic targets.
In contrast, in cells exposed to stress or development variables, TG2 acts as a unfavorable regulator in the contractile phenotype and promotes dedifferentiation. By way of example, TG2 induced an osteoblast like transformation of vascular smooth muscle cells major to vascular selleck chemicals calcification. The LRP5 six B catenin signaling pathway was implicated as a mediator of these TG2 effects in vascular smooth muscle cells. In parallel, TG2 amplified the dedifferentiation of aortic smooth muscle cells by PDGF because of TG2 induced amplification of PDGF PDGFR signaling in conjunction with increasing their survival, proliferation, and migration. Thus, on the surface of vascular smooth muscle cells, TG2 acts as a negative regulator of their phenotypic stability. Accumulation of TG2 in blood vessels may underlie the phenotypic transformation of these cells in vascular illnesses and the loss of blood vessel compliance. 5. 4. 7. Epithelial cells Like its effects on vascular smooth muscle cells, TG2 destabilizes mammary epithelial cells and confers stem cell like properties to both untransformed and transformed cells.