The secreted protein augurin is a novel modulator of canonical Wnt signalling involved in osteoblast differentiation

Abstract

The secreted protein augurin is a novel inhibitor of canonical Wnt signalling • Inactivation of the gene encoding augurin (Ecrg4) produced increased osteogenic differentiation of mouse calvarial osteoblasts • Genome-wide association studies showed that an intronic ECRG4 variant (rs66989638) is associated with height and osteoarthritis • Augurin is a new potential drug target to modulate Wnt signalling

Complex and pleiotropic signaling pathways regulated by the secreted protein augurin

“…We have recently shown that Ecrg4 expression is strongly increased during the process of osteoblast differentiation in vitro and that osteoblasts from Ecrg4 −/− mice have an accelerated differentiation, which indicates a role for augurin in osteoblast differentiation [ 37 ].…”

“…The suppression of GSK-3β activity leads to β-catenin accumulation into the cytoplasm and translocation to the nucleus, where it interacts with the TCF/LEF transcription factors to activate the transcription of their target genes (right panel). Augurin specifically represses the canonical Wnt/β-catenin signaling pathway, however through which receptor it exerts its action and the precise mechanisms of Wnt signaling repression remain to be unveiled [ 37 ] …”

“…Overall, these data led us to the hypothesis that augurin might be implicated in the Wnt signaling pathway. Indeed, we have recently provided evidence that augurin is a novel physiological modulator of canonical Wnt signaling involved in osteoblast differentiation [ 37 ]. We have shown that osteoblasts from Ecrg4 −/− mice displayed an accelerated differentiation compared to wild-type and upregulation of Wnt activation markers [ 37 ].…”

“…Indeed, we have recently provided evidence that augurin is a novel physiological modulator of canonical Wnt signaling involved in osteoblast differentiation [ 37 ]. We have shown that osteoblasts from Ecrg4 −/− mice displayed an accelerated differentiation compared to wild-type and upregulation of Wnt activation markers [ 37 ]. Furthermore, we could demonstrate that Ecrg4 is itself a negative Wnt target gene, being markedly downregulated by the treatment of osteoblast-like mouse MC3T3-E1 cells with Wnt3a and RSPO1 [ 37 ].…”

“…We have shown that osteoblasts from Ecrg4 −/− mice displayed an accelerated differentiation compared to wild-type and upregulation of Wnt activation markers [ 37 ]. Furthermore, we could demonstrate that Ecrg4 is itself a negative Wnt target gene, being markedly downregulated by the treatment of osteoblast-like mouse MC3T3-E1 cells with Wnt3a and RSPO1 [ 37 ]. In transient transfection assays in MC3T3-E1 cells, both mouse (mAug) and human augurin (hAug) significantly and specifically repressed activity of the Wnt-responsive TOPFLASH promoter upon stimulation with Wnt3a/RSPO1, the mutation of the putative furin cleavage site (R67A/K69A) in both mAug and hAug having no effects on the repression of TOPFLASH [ 37 ].…”