Factor XIIIA transglutaminase expression and secretion by osteoblasts is regulated by extracellular matrix collagen and the MAP kinase signaling pathway

Abstract

Osteoblast differentiation is regulated by the presence of collagen type I (COL I) extracellular matrix (ECM). We have recently demonstrated that Factor XIIIA (FXIIIA) transglutaminase (TG) is required by osteoblasts for COL I secretion and extracellular deposition, and thus also for osteoblast differentiation. In this study we have further investigated the link between COL I and FXIIIA, and demonstrate that COL I matrix increases FXIIIA levels in osteoblast cultures and that FXIIIA is found as cellular (cFXIIIA) and extacellular matrix (ecmFXIIIA) forms. FXIIIA mRNA, protein expression, cellular localization and secretion were enhanced by ascorbic acid (AA) treatment and blocked by dihydroxyproline (DHP) which inhibits COL I externalization. FXIIIA mRNA was regulated by the MAP kinase pathway. Secretion of ecmFXIIIA, and its enzymatic activity in conditioned medium, were also decreased in osteoblasts treated with the lysyl oxidase inhibitor β-aminopropionitrile, which resulted in a loosely packed COL I matrix. Osteoblasts secrete a latent, inactive dimeric ecmFXIIIA form which is activated upon binding to the matrix. Monodansyl cadaverine labeling of TG substrates in the cultures revealed that incorporation of the label occurred at sites where fibronectin co-localized with COL I, indicating that ecmFXIIIA secretion could function to stabilize newly deposited matrix. Our results suggest that FXIIIA is an integral part of the COL I deposition machinery, and also that it is part of the ECM-feedback loop, both of which regulate matrix deposition and osteoblast differentiation.

Biochemical characterization of a medaka (Oryzias latipes) orthologue for mammalian Factor XIII and establishment of a gene‐edited mutant

“…Expression in bone and esophagus was additionally revealed by the immunohistochemical analysis. Studies in mammals reported that FXIII is expressed in osteoblasts, chondrocyte, and preadipocyte cells [10][11][12], which is consistent with our present data. Our results support that FXIIIA plays multiple roles at several tissues including bone, while a recent report described that FXIIIA is not functionally expressed in bone [26].…”

Cellular Factor XIIIA Transglutaminase Localizes in Caveolae and Regulates Caveolin-1 Phosphorylation, Homo-oligomerization and c-Src Signaling in Osteoblasts

“…1B; the data shows that not all stainable FXIII-A is found to co-localize with Cav-1. The induction of FXIII-A upon differentiation treatment (DM media) was consistent with that observed in our previous studies (Al-Jallad et al 2011;Piercy-Kotb et al 2012;Wang et al 2014). …”

Reactive Oxygen Species Affect Transglutaminase Activity and Regulate Hematopoiesis in a Crustacean

“…Moreover, the down-regulation of TG2 inhibited angiogenesis in cell culture (36). In addition, osteoblast differentiation is regulated by the presence of collagen type I in the ECM, and TGase is required for collagen secretion and extracellular deposition, which controls osteoblast differentiation (37). TG2 can also associate with several ECM proteins and mediate interactions between the ECM and soluble growth factors through the regulation of integrins and growth factor receptors (38,39).…”