Interaction between ferroptosis and TNF-α: Impact in obesity-related osteoporosis

Xin Chen; Chao Liu; Rongcheng Yu; Ziqi Gan; Zhen Zhang; Zhengyuan Chen; Yuanbo Liu; Dongle Wu; Xinyi Yu; Chufeng Liu; Yang Cao

doi:10.1096/fj.202201958R

Interaction between ferroptosis and TNF-α: Impact in obesity-related osteoporosis

FASEB J. 2023 Jun;37(6):e22947. doi: 10.1096/fj.202201958R.

Authors

Xin Chen^{1

2}, Chao Liu^{1

2}, Rongcheng Yu^{1

2}, Ziqi Gan^{1

2}, Zhen Zhang^{1

2}, Zhengyuan Chen^{1

2}, Yuanbo Liu^{1

2}, Dongle Wu^{1

2}, Xinyi Yu^{1

2}, Chufeng Liu³, Yang Cao^{1

2}

Affiliations

¹ Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China.
² Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.
³ Stomatological Hospital, Southern Medical University, Guangzhou, China.

PMID: 37199646
DOI: 10.1096/fj.202201958R

Abstract

The relationship of obesity and osteoporosis has been widely studied over the past years. However, the implications of obesity for bone health remain controversial, and the underlying molecular mechanism is not yet fully understood. This study demonstrated that high-fat diet-induced obesity leads to significantly decreased bone volume/tissue volume (BV/TV), trabecular number (Tb.N), and cortical thickness (Ct.Th) of male rat femur after mechanical loading effects of body weight were controlled. HFD-induced obese rats exhibited attenuated expression of ferroptosis inhibitory protein SLC7A11 and GPX4 in bone tissues, which was correlated with elevated serum TNF-α concentration. Ferroptosis inhibitor administration could effectively rescue decreased osteogenesis-associated type H vessels and osteoprogenitors, and downregulate serum levels of TNF-α to ameliorate bone loss in obese rats. Since ferroptosis and TNF-α both affect bone and vessel formation, we further investigated the interaction between ferroptosis and TNF-α, and its impact in osteogenesis and angiogenesis in vitro. In human osteoblast-like MG63 and umbilical vein endothelial cells (HUVEC), TNF-α/TNFR2 signaling promoted cystine uptake and GSH biosynthesis to provide protection against low-dose ferroptosis inducer erastin. While, TNF-α/TNFR1 facilitated ferroptosis in the presence of high-dose erastin through ROS accumulation. Moreover, TNF-α regulated ferroptosis-induced osteogenic and angiogenic dysfunctions based on its ferroptosis regulatory role. Meanwhile, ferroptosis inhibitors could reduce intracellular ROS overproduction and enhance osteogenesis and angiogenesis in TNF-α-treated MG63 and HUVECs. This study revealed the interaction between ferroptosis and TNF-α and its impact in osteogenesis and angiogenesis, which provides new insights into the pathogenesis and regenerative therapy of obesity-related osteoporosis.

Keywords: GSH; TNF-α; ferroptosis; obesity; osteoporosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Endothelial Cells / metabolism
Ferroptosis*
Humans
Male
Obesity / metabolism
Osteoporosis* / metabolism
Rats
Reactive Oxygen Species
Tumor Necrosis Factor-alpha / metabolism

Substances

Tumor Necrosis Factor-alpha
Reactive Oxygen Species