FSH exacerbates bone loss by promoting osteoclast energy metabolism through the CREB-MDH2-NAD+ axis

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental Pub Date : 2025-01-27 DOI:10.1016/j.metabol.2025.156147

Jingqiu Chen , Yilin Liao , Yue Sheng, Hantao Yao, Ting Li, Zhenru He, Weng Wan Yue Ye, Mengjie Yin, Huilin Tang, Yaoyu Zhao, Peiqi Zhang, Yuting Wang, Xiazhou Fu, Yaoting Ji

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引用次数: 0

Abstract

Aims

Osteoclast energy metabolism is a promising target for treating diseases characterized by high osteoclast activity, such as osteoporosis. However, the regulatory factors involved in osteoclast bioenergetic processes are still in the early stages of being fully understood. This study reveals the effects of follicle-stimulating hormone (FSH) on osteoclast energy metabolism.

Methods

The Lyz2-Cre-Flox model selectively deletes FSH receptor (FSHR) from osteoclast precursor cells to generate Fshr^f/f; Lyz2-Cre (Fshr^f/f; Cre) mice. Bone quality was assessed using micro-computed tomography, histomorphometric analysis, and dual-fluorescence labeling. The in vitro assays measured oxygen consumption rate, extracellular acidification rate, pyruvate content, and mitochondrial membrane potential to determine metabolic flux. RNA-seq, LC-MS, dual-luciferase reporter assays, and chromatin immunoprecipitation (ChIP) assays were used to elucidate the underlying mechanisms.

Results

FSHR deficiency in osteoclasts protected bone from resorption under normal and ovariectomized conditions. FSHR-deficient osteoclasts have reduced nicotinamide adenine dinucleotide (NAD⁺) levels, impairing osteoclast activity and energy metabolism. Mechanistically, FSH influenced NAD⁺ levels via the CREB/MDH2 axis. Treatment with FSH monoclonal antibodies rescued bone loss in OVX mice and reduced bone marrow NAD⁺ levels.

Conclusions

Targeting FSH may be a promising metabolic modulation strategy for treating osteoporosis and other diseases associated with high osteoclast activity.

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来源期刊

Metabolism: clinical and experimental 医学-内分泌学与代谢

CiteScore

18.90

自引率

3.10%

发文量

310

审稿时长

16 days

期刊介绍： Metabolism upholds research excellence by disseminating high-quality original research, reviews, editorials, and commentaries covering all facets of human metabolism. Consideration for publication in Metabolism extends to studies in humans, animal, and cellular models, with a particular emphasis on work demonstrating strong translational potential. The journal addresses a range of topics, including: - Energy Expenditure and Obesity - Metabolic Syndrome, Prediabetes, and Diabetes - Nutrition, Exercise, and the Environment - Genetics and Genomics, Proteomics, and Metabolomics - Carbohydrate, Lipid, and Protein Metabolism - Endocrinology and Hypertension - Mineral and Bone Metabolism - Cardiovascular Diseases and Malignancies - Inflammation in metabolism and immunometabolism