The role of the Nrf2/Keap1 signaling cascade in mechanobiology and bone health

Abstract

In conjunction with advancements in modern medicine, bone health is becoming an increasingly prevalent concern among a global population with an ever-growing life expectancy. Countless factors contribute to declining bone strength, and age exacerbates nearly all of them. The detrimental effects of bone loss have a profound impact on quality of life. As such, there is a great need for full exploration of potential therapeutic targets that may provide antiaging benefits and increase the life and strength of bone tissues. The Keap1-Nrf2 pathway is a promising avenue of this research. The cytoprotective and antioxidant functions of this pathway have been shown to mitigate the deleterious effects of oxidative stress on bone tissues, but the exact cellular and molecular mechanisms by which this occurs are not yet fully understood. Presently, refined animal and loading models are allowing exploration into the effect of the Keap1-Nrf2 pathway in a tissue-specific or even cell-specific manner. In addition, Nrf2 activators currently undergoing clinical trials can be utilized to investigate the particular cellular mechanisms at work in this cytoprotective cascade. Although the timing and dosing of treatment with Nrf2 activators need to be further investigated, these activators have great potential to be used clinically to prevent and treat osteoporosis.

Keywords: Antioxidants; Keap1; Mechanobiology; Nrf2; Osteoporosis.

Fig. 1

Molecular mechanisms of the Keap1-Nrf2 pathway. Under basal conditions, Nrf2 is bound by its sequestering protein, Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. Keap1 prevents the translocation of Nrf2 to the nucleus and marks it for proteosomal degradation. Under stressed conditions, the cysteine residues which maintain the association with Nfr2 are oxidized, modifying their shape and releasing Nrf2. Unbound Nrf2 is then free to translocate to the nucleus for activation, initiating the cytoprotective signaling cascade.

Fig. 2

Biological factors contributing to and resulting from Nrf2 expression. Pointed arrows indicate positive regulation. Barred arrows indicate inhibition. Factors which influence Nrf2 expression are displayed in blue, while downstream implications of Nrf2 expression are shown in orange. Lists below bubbles display specific compounds involved, with red font representing inhibition and black font indicating activation (Kensler et al., 2007; Merry and Ristow, 2016; Itoh et al., 2010; Domazetovic et al., 2017; Huang et al., 2015; Alam et al., 1999; Thimmulappa et al., 2002; Chen and Maltagliati, 2017; Ajiboye et al., 2014; Zhou et al., 2014; Yamaguchi et al., 2018; Liu et al., 2018; Florczyk et al., 2014; Toledo-Arruda et al., 2020; Zhou et al., 2020; Cheng et al., 2016; Tsukimoto et al., 2010; Liu et al., 2019b; Rysava et al., 2020; Wang et al., 2020b; McDonald et al., 2010; Bellanti et al., 2013; Zimta et al., 2019).