FABP4 inhibition suppresses bone resorption and protects against postmenopausal osteoporosis in ovariectomized mice

Qian Xie (), Xiangfu Du, Jianhui Liang, Yanni Shen, Yufan Ling, Zhengji Huang, Zekai Ke, Tai Li, Bing Song, Tailin Wu (), Yan Wang () and Huiren Tao ()
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Qian Xie: Chinese Academy of Sciences
Xiangfu Du: Chinese Academy of Sciences
Jianhui Liang: Chinese Academy of Sciences
Yanni Shen: Chinese Academy of Sciences
Yufan Ling: Chinese Academy of Sciences
Zhengji Huang: Shenzhen University General Hospital
Zekai Ke: Shenzhen University General Hospital
Tai Li: Chinese Academy of Sciences
Bing Song: Chinese Academy of Sciences
Tailin Wu: The University of Hong Kong-Shenzhen Hospital
Yan Wang: Chinese Academy of Sciences
Huiren Tao: The University of Hong Kong-Shenzhen Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Postmenopausal osteoporosis (PMOP) is a condition in women caused by estrogen deficiency, characterized by reduced bone mass and increased fracture risk. Fatty acid-binding protein 4 (FABP4), a lipid-binding protein involved in metabolism and inflammation, has emerged as a key regulator in metabolic disorders and bone resorption; however, its direct role in PMOP remains unclear. Here, we show that serum FABP4 levels in PMOP patients negatively correlate with bone mineral density, a trend also observed in ovariectomized mice. FABP4 promotes osteoclast formation and bone resorption without affecting osteoblast differentiation. The FABP4 inhibitor BMS309403 suppresses osteoclast differentiation by modulating calcium signaling and inhibiting the Ca2+-Calcineurin-NFATc1 pathway. Oral BMS309403 increases bone mineral density in ovariectomized mice, though less effectively than alendronate. Notably, bone-targeted delivery of BMS309403 achieves comparable efficacy to alendronate. In this work, we demonstrate that FABP4 is a critical mediator in PMOP and that its inhibition offers a promising therapeutic strategy.

Date: 2025
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DOI: 10.1038/s41467-025-59719-w

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