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.

Keywords: Angiogenesis; Bone defects; Endoplasmic reticulum stress; Exosome; High glucose; Inflammation; Osteogenesis; Unfolded protein response.

Fig. 1

Major UPR pathways initiated in the ER [38]. RIDD: regulated IRE1ɑ-dependent decay; TRAF: tumor necrosis factor receptor associated factor; ERAD: ER-associated protein degradation; PP1: protein phosphatase 1; CreP: constitutive repressor of eIF2ɑ phosphorylation; DR5: death receptor 5; TXNIP: thioredoxin-interacting protein; IP3R: inositol-1,4,5-triphosphate receptor; BI-1: Bax inhibitor-1; GADD34: growth arrest and DNA damage inducible gene 34. Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation, and functions of the unfolded protein response. Nat Rev Mol Cell Biol. 2020;21(8):421–38. Copyright© The Authors 2020. Published by Springer Ltd

Fig. 2

PRP-Exos rescued cells from GC-induced apoptosis via the Akt/Bcl-2 pathway [132]. Tao SC, Yuan T, Rui BY, Zhu ZZ, Guo SC, Zhang CQ. Exosomes derived from human platelet-rich plasma prevent apoptosis induced by glucocorticoid-associated endoplasmic reticulum stress in rat osteonecrosis of the femoral head via the Akt/Bad/Bcl-2 signal pathway. Theranostics. 2017;7(3):733–50. Copyright© The Authors 2017. Published by Ivyspring International Publisher