Unraveling the role of FoxOs in bone--insights from mouse models

Abstract

The FoxO subfamily of forkhead transcription factors plays a critical role in a variety of physiological processes including metabolism, differentiation, proliferation, apoptosis and protection from stress. FoxO activity is inhibited by growth factors and the insulin signaling pathways and stimulated by nutrient depletion and a plethora of reactive oxygen species (ROS)-induced post-translational modifications. Recent studies have uncovered a fundamental role for FoxOs in skeletal homeostasis. In cells of the osteoblast lineage, FoxOs modulate redox balance, protein synthesis, and differentiation through the activation of specific gene programs and interaction with other transcription factors and co-factors such as β-catenin, ATF-4, and Runx2. FoxO activation also attenuates osteoclastogenesis through both cell autonomous and indirect mechanisms. In this review I discuss recent advances in the understanding of FoxO specific actions in osteoblast progenitors, osteoblasts, and osteoclast, as well as the implications of FoxO activation for age-related skeletal involution.

Figure 1. Activation of FoxO transcription factors by ROS

Phosphorylation of FoxOs by Akt leads to the nuclear export of FoxOs and inhibition of FoxO-mediated transcription. ROS, via JNK or Mst1 activation, phosphorylate FoxOs at different residues, promote FoxOs nuclear translocation, and activation of transcription. ROS also promote FoxOs acetylation and deacetylation via Sirt1 activation. Finally, ROS promote the association between FoxOs and β-catenin which enhances FoxO-mediated transcription. Bim-1, Bcl-2-like protein 11; DBE, DAF-16 binding element; Fas-L, Fas ligand; GADD45, Growth Arrest and DNA Damage 45; MnSOD, Manganese Superoxide Dismutase.

Figure 2. Diverse role of FoxOs in osteoblast lineage cells

(a) FoxO3 activity decreases ROS levels and promote osteoblast survival. FoxO1 associates with ATF4 to promote protein synthesis, decrease ROS levels and stimulate proliferation. (b) Activation of the canonical Wnt signaling by Wnt proteins prevents the proteasomal degradation of β-catenin and promotes its association with the TCF/Lef family of transcription factors and the expression of Wnt target genes. Activation of FoxO mediated transcription by ROS promotes the binding of FoxO to β-catenin, thus diverting the limited pool of from TCF/Lef to FoxO mediated transcription and thereby decreases osteoblastogenesis.

Figure 3. FoxOs decrease osteoclast numbers and bone resorption

FoxOs play an essential role in the response to physiologic oxidative stress and thereby promote survival and self-renewal of hematopoietic stem cells. In contrast, activation of FoxO in osteoclast precursor cells attenuates resorption and increases bone mass. In line with a cell autonomous inhibitory action of FoxOs on osteoclast generation and/or survival, Akt and Mst1 kinase activity promote and attenuate osteoclast number, respectively. However, it is unknown whether the actions Akt and Mst1 in osteoclastic cells are mediated by FoxOs. FoxO activity in osteoblast also decreases osteoclast number via increased Opg expression or other mechanisms.