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  3. Lif-deficiency promote systemic Iron metabolism disorders and increases the susceptibility of osteoblasts to ferroptosis

Lif-deficiency promote systemic Iron metabolism disorders and increases the susceptibility of osteoblasts to ferroptosis

  • Bone. 2024 Dec:189:117266. doi: 10.1016/j.bone.2024.117266.
Yu Zhang 1,  Yaqi Cong 1,  Juan Du 1,  Donghua Guo 1,  Jing Huang 1,  Junchen Pan 1,  Youde Liang 2,  Jiali Zhang 1,  Zhou Ye 3,  Yi Liu 4,  Yi Zhou 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
  • 2 The People's Hospital of Baoan Shenzhen, Shenzhen, China.
  • 3 Applied Oral Sciences and Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong Kong Special Administrative Region.
  • 4 Department of Stomatology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi 435002, China. Electronic address: liuyly2024@163.com.
  • 5 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Center for Prosthodontics and Implant Dentistry, Optics Valley Branch, School and Hospital of Stomatology, Wuhan University, Wuhan, China. Electronic address: dryizhou@whu.edu.cn.
PMID: 39341481 DOI: 10.1016/j.bone.2024.117266
Abstract

Leukemia Inhibitory Factor (LIF) is a multifunctional cytokine that plays a crucial role in various biological processes. However, LIF involvement in iron metabolism remains almost unexplored. This study aimed to explore the impact of LIF on systemic iron transportation and its potential role in Ferroptosis in osteoblasts. We observed that the Lif-deficient (Lif-/-) mice is characterized by a reduction in bone mass and a decrease in bone mineral density compared with wild-type (WT) mice. Energy-dispersive X-ray spectroscopy revealed a marked increase in iron content on the surface of femurs from Lif-/- mice. Meanwhile, iron stores test lower iron levels in the spleens and higher levels in the femurs of Lif-/- mice. Besides, Lif-/- mice display increased levels of serum iron, total iron-binding capacity, unsaturated iron-binding capacity, and transferrin saturation and serum ferritin relative to WT mice. Hepcidin mRNA expression reduction in the liver of Lif-/- mice. It also holds true in the AML-12 hepatocyte cell line after Lif-knockdown. Immunohistochemistry and RT-PCR revealed elevated Ferroportin (FPN) in duodenal cells of Lif-/- mice. Lif-deficiency decreases SLC7A11 levels in osteoblasts. In addition, overexpression of LIF downregulates CD71, DCYTB, and DMT1, thereby reducing iron uptake in iron-overloaded cells. Femur immunohistochemistry (IHC) revealed increased ACSL4 and decreased GPX4 and SLC7A11, indicating an increase in Ferroptosis of osteoblasts in Lif-/- mice. Whole-transcriptome Sequencing showed gene expression changes after Lif-knockdown, exhibiting a negative correlation with genes involved in long-chain fatty acid transport, mitochondrial organization, and the p38 MAPK signaling pathway. These results demonstrate that Lif-deficiency alter systemic iron metabolism and increases the susceptibility of osteoblasts to Ferroptosis.

Keywords

Ferroptosis; Hepcidin; Leukemia inhibitory factor; Osteoporosis; iron transportation.

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