Endoplasmic reticulum stress: a novel targeted approach to repair bone defects by regulating osteogenesis and angiogenesis

Abstract

Bone regeneration therapy is clinically important, and targeted regulation of endoplasmic reticulum (ER) stress is important in regenerative medicine. The processing of proteins in the ER controls cell fate. The accumulation of misfolded and unfolded proteins occurs in pathological states, triggering ER stress. ER stress restores homeostasis through three main mechanisms, including protein kinase-R-like ER kinase (PERK), inositol-requiring enzyme 1ɑ (IRE1ɑ) and activating transcription factor 6 (ATF6), collectively known as the unfolded protein response (UPR). However, the UPR has both adaptive and apoptotic effects. Modulation of ER stress has therapeutic potential for numerous diseases. Repair of bone defects involves both angiogenesis and bone regeneration. Here, we review the effects of ER stress on osteogenesis and angiogenesis, with emphasis on ER stress under high glucose (HG) and inflammatory conditions, and the use of ER stress inducers or inhibitors to regulate osteogenesis and angiogenesis. In addition, we highlight the ability for exosomes to regulate ER stress. Recent advances in the regulation of ER stress mediated osteogenesis and angiogenesis suggest novel therapeutic options for bone defects.

Paeoniflorin Induces ER Stress-Mediated Apoptotic Cell Death by Generating Nox4-Derived ROS under Radiation in Gastric Cancer

“…Previous studies have shown that ER stress response activates the UPR and induces apoptosis and cell death in various cancer cell types [60,61]. ER stress plays a crucial role in various cellular environments and regulates cell survival and cell death [62]. The ER lumen is important in post-translational modification, protein folding of secretory proteins, and maintaining calcium and redox conditions for cellular homeostasis.…”

“…However, if this process fails, the accumulation of unfolded proteins initiates ER stress via the activation of ER transmembrane proteins, such as PERK, IRE1α, and ATF6 [63]. Mild ER stress contributes to cell homeostasis via the activation of signaling pathways for cell survival [62]. However, strong or accumulated ER stress induces apoptotic cell death via the activation of the CHOP-DR4/5-caspase-8/9-caspase-3 axis in various cancer cell lines, indicating a potential strategy for tumor therapy [60,64].…”

IRX5 suppresses osteogenic differentiation of hBMSCs by inhibiting protein synthesis

“…Osteogenesis of hBMSCs involves three steps: commitment to osteoblast lineage, extracellular matrix secretion and maturation, and matrix mineralization. BMSCs possess robust anabolic capacity and high protein synthesis rate during osteoblast differentiation, to secret large amount extracellular matrix proteins, such as type Ⅰ collagen protein (Karner et al, 2017;Wu et al, 2023). Ribosome biogenesis ensures protein synthesis, which is integrated with regulators of bone formation during skeletal development.…”

“…The mTOR is a serine/threonine protein kinase that integrates signals from both nutrients and growth factors to govern numerous fundamental cellular processes via two distinct protein complexes known as mTORC1 and mTORC2 (Chen & Long, 2018). Recent genetic studies in mice have firmly established the pivotal roles of mTORC1 pathways in the regulation of various facets of skeletal development and maintenance, including the transition of preosteoblasts to mature osteoblasts (Chen et al, 2014;Xian et al, 2012). Knockout of Raptor, a component in mTORC1 complex, in pre-osteoblasts with Osx-Cre caused osteopenia in mice, mainly due to a defect in matrix synthesis and bone mineralization without impacting autophagy (Chen & Long, 2015;Fitter et al, 2017).…”