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Review
. 2021 Apr;54(4):e13011.
doi: 10.1111/cpr.13011. Epub 2021 Feb 21.

PERK signaling pathway in bone metabolism: Friend or foe?

Jiachao Guo  1 , Ranyue Ren  2 , Kai Sun  2 , Jinpeng He  1 , Jingfan Shao  1
Affiliations
Review

PERK signaling pathway in bone metabolism: Friend or foe?

Jiachao Guo et al. Cell Prolif. 2021 Apr.

Abstract

Osteoblasts and osteoclasts participate in the process of bone remodelling to meet the needs of normal growth and development or repair pathological damage. Endoplasmic reticulum stress (ER stress) can break the intracellular homeostasis of osteoclasts and osteoblasts, which is closely related to abnormal bone remodelling. The double-stranded RNA-dependent protein kinase (PKR)-like ER kinase (PERK) is a key transmembrane protein that regulates ER stress, and growing evidence suggests that the PERK pathway plays a crucial role in regulating bone metabolism under both physiological and pathological conditions. Based on the current findings, we summarized the main mechanisms involved in bone metabolism downstream of the PERK pathway, among which elF2α, FOXO1, CaN, Nrf2 and DAG play a role in regulating the differentiation of osteoblasts and osteoclasts. Importantly, strategies by the regulation of PERK pathway exert beneficial effects in preclinical trials of several bone-related diseases. Given the importance and novelty of PERK pathway, we provide an overview and discuss the roles of PERK pathway in regulating bone metabolism and its impact on bone-related diseases. We hope that the development of research in this field will bring a bright future for the treatment of bone-related diseases.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

FIGURE 1
FIGURE 1
A brief diagram of the PERK signalling pathway. While ER stress is induced, unfolded protein competitively binds to BIP, causing BIP to dissociate from PERK and PERK is then phosphorylated. Phosphorylated PERK is activated and makes the downstream Nrf2 dislocate with Keap1 and activate, the activity of CaN increase, elF2α, DAG and FOXO1 phosphorylate, and they further play different roles respectively. Green squares indicate the expression of the genes
FIGURE 2
FIGURE 2
Effects of downstream changes caused by activation of PERK on osteoblastogenesis. Phosphorylated elF2α, Nrf2, DAG, FOXO1 and enhanced activity of CaN have different impacts on osteogenic differentiation, respectively. Highly related diseases are also showed. Green squares indicate the expression of the genes
FIGURE 3
FIGURE 3
Impact of PERK signalling activation on osteoclastogenesis. PERK activation‐induced phosphorylated elF2α, Nrf2, DAG, FOXO1 and enhanced activity of CaN play different roles on osteoclast differentiation, respectively. Strongly associated diseases are exhibited. Green squares indicate the expression of the genes
See this image and copyright information in PMC

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