Exosomes derived from vascular endothelial cells antagonize glucocorticoid‐induced osteoporosis by inhibiting ferritinophagy with resultant limited ferroptosis of osteoblasts

Abstract

High dose and long-term steroid treatment can alter antioxidative ability and decrease the viability and function of osteoblasts, leading to osteoporosis and osteonecrosis. Ferroptosis, a new type of cell death characterized by excessive lipid peroxidation due to the downregulation of GPX4 and system X c− , is involved in glucocorticoid-induced osteoporosis. Endothelial cell-secreted exosomes (EC-Exos) are important mediators of cell-to-cell communication and are involved in many physiological and pathological processes. However, the effect of EC-Exos on osteoblasts exposed to glucocorticoids has not been reported. Here, we explored the role of EC-Exos in glucocorticoid-induced osteoporosis. In vivo and in vitro experiments indicated that EC-Exos reversed the glucocorticoid-induced osteogenic inhibition of osteoblasts by inhibiting ferritinophagy-dependent ferroptosis.

Ferroptosis and Its Potential Role in Metabolic Diseases: A Curse or Revitalization?

“…A recent study supported that ferritin-containing multivesicular bodies and exosomes are qualified to discharge iron driven by prominin2, illuminating a new mode to prevent ferroptosis (Brown et al, 2019). What merits attention is that the endothelial cell-secreted exosome has proven to throw a wrench in the glucocorticoid-induced osteoporosis process by abating ferritinophagy (Yang et al, 2021). Dysregulation of iron homeostasis and metabolism is substantiated to have a close connection to diverse metabolic diseases, such as diabetes (Dubey et al, 2020), obesity, metabolic syndrome (Gonzalez-Dominguez et al, 2020), osteoporosis (Che et al, 2020;Sato et al, 2020) and AS (Wunderer et al, 2020).…”

“…Another study sustained these results. Due to the ferroptosis-induced role played by glucocorticoids in osteoblasts (Lu et al, 2019), Yang et al (2021) originally found that exosomes derived from vascular endothelial cells (EC-Exos) counteract this process both in vitro and in vivo by decreasing NCOA4 expression to suppress ferritinophagy and simultaneously targeting the Keap1-Nrf2-HO-1/NQO-1 pathway to inhibit lipid oxidation, though the specific signal has not yet been elucidated. Some drugs that target osteoporosis may actualize a ferroptotic role during the therapeutic mechanism, which, in our perspective, is reasonable to surmise, but not yet visible.…”

Exosomes: A Friend or Foe for Osteoporotic Fracture?

“…Song et al found that miR-155 loaded in endothelial cells-derived exosomes suppressed osteoclasts' differentiation and activation by several targets, like Spi1, microphthalmia-associated transcription factor (Mitf), and suppressor of cytokine signaling 1 (Socs1) (67). Furthermore, endothelial cells-derived exosomes could rescue the glucocorticoid-induced osteogenic suppression of osteoblasts by inhibiting ferritinophagy-dependent ferroptosis (68). Hence, endothelial cells-derived exosomes might be promising and biocompatible nanomedicine for OP.…”

The Potential Therapeutic Role of Mesenchymal Stem Cells-Derived Exosomes in Osteoradionecrosis

“…However, excessive ferroptosis also occur in normal cells, ischemia-reperfusion injury, kidney failure, neurodegeneration, and other diseases [ 56 ]. If ferroptosis occurs in the osteoblasts, osteoporosis and osteonecrosis will appear [ 84 ]. Exosomes derived from mouse vascular endothelial cells can reverse osteoporosis by inhibiting osteoblast ferroptosis [ 84 ].…”

“…If ferroptosis occurs in the osteoblasts, osteoporosis and osteonecrosis will appear [ 84 ]. Exosomes derived from mouse vascular endothelial cells can reverse osteoporosis by inhibiting osteoblast ferroptosis [ 84 ]. However, there are insufficient clinical trials and basic experiments to prove the relationship between ferroptosis and ORN.…”