Activation of osteoblast ferroptosis via the METTL3/ASK1‐p38 signaling pathway in high glucose and high fat (HGHF)‐induced diabetic bone loss

Abstract

Diabetes mellitus (DM) and osteoporosis are two common diseases that may develop as a cause-and-effect relationship since the incidence of osteoporotic fractures is significantly increased in DM patients. However, the pathophysiology of diabetic osteoporosis is yet to be clearly understood. Iron overload has been reported to lead to bone loss and closely related to osteoporosis. In this study, we hypothesized that high glucose and high fat (HGHF) may induce osteoblastic ferroptosis for the pathogenesis of diabetic osteoporosis and explored the possible molecular mechanisms behind. Using the diabetic rat model established by HGHF feeding with a subsequent intraperitoneal injection of a single low dose of streptozocin, we found that the serum ferritin level (a biomarker for body iron store) was significantly elevated in HGHF-fed rats and the expression of SLC7A11 and GPX4 (inhibitory marker proteins for ferroptosis) was markedly attenuated in the bone tissue of the rats with diabetic bone loss as compared to the normal rats. In an osteoblast cell model, treatment of pre-osteoblastic MC3T3-E1 cells with high glucose and palmitic acid (HGPA) not only suppressed osteoblast differentiation and mineralization but also triggered ferroptosis-related osteoblastic cell death. m 6 A-seq revealed that m 6 A methylation on ASK1 was 80.9-fold higher in HGPA-treated cells. The expression of p-ASK1 and p-p38 was also significantly elevated in the HGPA-treated cells. Knockout of METTL3 (methyltransferaselike 3), one of the major m 6 A methyltransferases, in MC3T3-E1 cells not only abrogated HGPA-induced activation of ASK1-p38 signaling pathway but also attenuated the level of ferroptosis. Therefore, HGHF-induced ferroptosis in osteoblasts may be the main cause of osteoporosis in DM via activation of METTL3/ How to cite this article: Lin Y, Shen X, Ke Y, et al. Activation of osteoblast ferroptosis via the METTL3/ASK1-p38 signaling pathway in high glucose and high fat (HGHF)-induced diabetic bone loss.

Targeting Ferroptosis as a Novel Approach to Alleviate Aortic Dissection

“…Ma et al found that the m 6 A reader YTHDC2 promotes SLC7A11 mRNA decay by binding to m 6 A-modified SLC7A11 mRNA [32]. Consistent with our results, Lin et al also showed that knockout of METTL3 in pre-osteoblastic MC3T3-E1 cells attenuated the level of ferroptosis [44]. However, Xu et al revealed that METTL3-mediated m 6 A modification of SLC7A11 mRNA was read by YTHDF1, which promoted the translation of SLC7A11 mRNA to inhibit lung adenocarcinoma cell ferroptosis [45].…”

Ferroptosis as a Novel Therapeutic Target for Diabetes and Its Complications

“…Recent studies have shown that Fer-1 and DFO block ferroptosis induced by HG and palmitic acid (HGPA) in MC3T3-E1 cells. The mechanism of high glucose and high fat (HGHF)-induced ferroptosis in osteoblasts is related to the activation of the METTL3/ASK1-p38 signaling pathway ( 114 ). Morphological changes of mitochondrial are the important hallmark of ferroptosis, and studies have shown that mitochondria play an important role in the regulation of ferroptosis via regulation of energetic metabolism, iron metabolism, and other pathways ( 115 , 116 ).…”

The Regulatory Role of Ferroptosis in Bone Homeostasis

“…Furthermore, the relationship between ferroptosis and glucocorticoid-induced osteoporosis (GIOP) has been well investigated [ 62 ]. For example, a recent study [ 47 ] reported that high-dose dexamethasone (10 μ M) can induce ferroptosis of OB by inhibiting the expression of GPX4 and system Xc − .…”

“…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]. For example, a recent study [47] reported that high-dose dexamethasone (10 μM) can induce ferroptosis of OB by inhibiting the expression of GPX4 and system Xc -.…”