Targeting Ferroptosis Suppresses Osteocyte Glucolipotoxicity and Alleviates Diabetic Osteoporosis

Overview

Journal Bone Res

Specialties Endocrinology
Orthopedics

Date 2022 Mar 9

PMID 35260560

Authors

Yiqi Yang

Yixuan Lin

Minqi Wang

Kai Yuan

Qishan Wang

Pei Mu

Jingke Du

Zhifeng Yu

Shengbing Yang

Kai Huang

Yugang Wang

Hanjun Li

Tingting Tang

Affiliations

Soon will be listed here.

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.

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