Tobacco toxins induce osteoporosis through ferroptosis
Zheng Jing,
Yuzhou Li,
He Zhang,
Tao Chen,
Jinrui Yu,
Xinxin Xu,
Yulong Zou,
Xu Wang,
Kai Xiang,
Xuerui Gong,
Ping He,
Yiru Fu,
Mingxing Ren,
Ping Ji,
Sheng Yang
Affiliations
Zheng Jing
Stomatological Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
Yuzhou Li
Stomatological Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
He Zhang
Stomatological Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
Tao Chen
Stomatological Hospital of Chongqing Medical University, Chongqing, China
Jinrui Yu
Stomatological Hospital of Chongqing Medical University, Chongqing, China
Xinxin Xu
Stomatological Hospital of Chongqing Medical University, Chongqing, China
Yulong Zou
Department of Orthopedics, Second Affiliated Hospital of Chongqing Medical University, China
Xu Wang
Stomatological Hospital of Chongqing Medical University, Chongqing, China
Kai Xiang
Stomatological Hospital of Chongqing Medical University, Chongqing, China
Xuerui Gong
Stomatological Hospital of Chongqing Medical University, Chongqing, China
Ping He
Stomatological Hospital of Chongqing Medical University, Chongqing, China
Yiru Fu
Stomatological Hospital of Chongqing Medical University, Chongqing, China
Mingxing Ren
Stomatological Hospital of Chongqing Medical University, Chongqing, China
Ping Ji
Stomatological Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China; Corresponding author. Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China.
Sheng Yang
Stomatological Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China; Corresponding author. Stomatological hospital of Chongqing Medical University , 426 Songshi North Road, Yubei District, Chongqing, 401147, China.
Clinical epidemiological studies have confirmed that tobacco smoking disrupts bone homeostasis and is an independent risk factor for the development of osteoporosis. The low viability and inferior osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) are important etiologies of osteoporosis. However, few basic studies have elucidated the specific mechanisms that tobacco toxins devastated BMSCs and consequently induced or exacerbated osteoporosis. Herein, our clinical data showed the bone mineral density (BMD) values of femoral neck in smokers were significantly lower than non-smokers, meanwhile cigarette smoke extract (CSE) exposure led to a significant decrease of BMD in rats and dysfunction of rat BMSCs (rBMSCs). Transcriptomic analysis and phenotype experiments suggested that the ferroptosis pathway was significantly activated in CSE-treated rBMSCs. Accumulated intracellular reactive oxygen species activated AMPK signaling, furtherly promoted NCOA4-mediated ferritin-selective autophagic processes, increased labial iron pool and lipid peroxidation deposition, and ultimately led to ferroptosis in rBMSCs. Importantly, in vivo utilization of ferroptosis and ferritinophagy inhibitors significantly alleviated BMD loss in CSE-exposed rats. Our study innovatively reveals the key mechanism of smoking-related osteoporosis, and provides a possible route targeting on the perspective of BMSC ferroptosis for future prevention and treatment of smoking-related bone homeostasis imbalance.
