Targeting ferroptosis suppresses osteocyte glucolipotoxicity and alleviates diabetic osteoporosis

Abstract

Diabetic osteoporosis (DOP) is the leading complication continuously threatening the bone health of patients with diabetes. A key pathogenic factor in DOP is loss of osteocyte viability. However, the mechanism of osteocyte death remains unclear. Here, we identified ferroptosis, which is iron-dependent programmed cell death, as a critical mechanism of osteocyte death in murine models of DOP. The diabetic microenvironment significantly enhanced osteocyte ferroptosis in vitro, as shown by the substantial lipid peroxidation, iron overload, and aberrant activation of the ferroptosis pathway. RNA sequencing showed that heme oxygenase-1 (HO-1) expression was notably upregulated in ferroptotic osteocytes. Further findings revealed that HO-1 was essential for osteocyte ferroptosis in DOP and that its promoter activity was controlled by the interaction between the upstream NRF2 and c-JUN transcription factors. Targeting ferroptosis or HO-1 efficiently rescued osteocyte death in DOP by disrupting the vicious cycle between lipid peroxidation and HO-1 activation, eventually ameliorating trabecular deterioration. Our study provides insight into DOP pathogenesis, and our results provide a mechanism-based strategy for clinical DOP treatment.

Fat Extract Modulates Calcium Signaling and Protects Against Hyperactive Osteoclastogenesis in Bone Remodeling with Antioxidant Capacity

“…However, the beneficial role of fat products remains debatable. Obesity severely impairs skeletal health and serum lipid levels are inversely correlated with bone mass [28]. In contrast, a study by Kajimura et al .…”

Ferroptosis, necroptosis, and pyroptosis in the occurrence and development of ovarian cancer

“…Inhibition of nitrogen fixation 1 (NFS1), which provides sulfur from cysteine for the synthesis of iron-sulfur clusters, activates the iron starvation response by simultaneously increasing transferrin receptor (TFRC) expression and degrading ferritin heavy chain 1 (FTH1), causing an increase in free iron ions, thereby making cells sensitive to ferroptosis activator ( 53 – 55 ). Overactivated heme oxygenase 1 increases intracellular free iron content and enhances ferroptosis effect by degrading hemoglobin into free iron, biliverdin, and carbon monoxide ( 56 – 58 ). Nuclear receptor coactivator 4 (NCOA4) recognizes intracellular after ferritin recognition, and ferritin transfers stored ferric ions to the autophagosome for degradation, which, in turn, releases ferric ions into the cytoplasm to become free iron, a process also known as iron autophagy ( 59 , 60 ).…”

The Regulatory Role of Ferroptosis in Bone Homeostasis

“…It has been reported that ferroptosis is an important form of OCT death, which can be reversed by targeting the inhibition of ferroptosis signaling pathways [ 52 ]. Yang et al [ 53 ] found that a hyperglycemic microenvironment is capable of promoting lipid peroxidation and iron overload, thereby inducing osteocyte ferroptosis. Furthermore, RNA sequencing results indicated that heme oxygenase-1 (HO-1) is overexpressed in ferroptotic osteocytes, suggesting that HO-1 is essential for osteocyte ferroptosis.…”

“…Yang et al [53] found that a hyperglycemic microenvironment is capable of promoting lipid peroxidation and iron overload, thereby inducing osteocyte ferroptosis. Furthermore, RNA sequencing results indicated that heme oxygenase-1 (HO-1) is overexpressed in ferroptotic osteocytes, suggesting that HO-1 is essential for osteocyte ferroptosis.…”

“…Similarly, in a murine model of diabetic osteoporosis (DOP), the researchers verified the important role of ferroptosis in DOP-induced OCT death. Mechanistically, activation of Nrf2/HO-1 signaling could lead to lipid peroxidation and cell ferroptosis, suggesting that targeting inhibition of OCT ferroptosis may be a potential therapeutic strategy for DOP treatment [53]. Furthermore, the relationship between ferroptosis and glucocorticoid-induced osteoporosis (GIOP) has been well investigated [62].…”