TIEG1 modulates β-catenin sub-cellular localization and enhances Wnt signaling in bone.

We have previously demonstrated that TGF beta Inducible Early Gene-1 (TIEG1), also known as KLF10, plays important roles in mediating skeletal development and homeostasis in mice. TIEG1 has also been identified in clinical studies as one of a handful of genes whose altered expression levels or allelic variations are associated with decreased bone mass and osteoporosis in humans. Here, we provide evidence for the first time that TIEG1 is involved in regulating the canonical Wnt signaling pathway in bone through multiple mechanisms of action. Decreased Wnt signaling in the absence of TIEG1 expression is shown to be in part due to impaired beta-catenin nuclear localization resulting from alterations in the activity of AKT and GSK-3 beta. We also provide evidence that TIEG1 interacts with, and serves as a transcriptional co-activator for, Lef1 and beta-catenin. Changes in Wnt signaling in the setting of altered TIEG1 expression and/or activity may in part explain the observed osteopenic phenotype of TIEG1 KO mice as well as the known links between TIEG1 expression levels/allelic variations and patients with osteoporosis.